NZ626473B2 - Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders - Google Patents
Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders Download PDFInfo
- Publication number
- NZ626473B2 NZ626473B2 NZ626473A NZ62647312A NZ626473B2 NZ 626473 B2 NZ626473 B2 NZ 626473B2 NZ 626473 A NZ626473 A NZ 626473A NZ 62647312 A NZ62647312 A NZ 62647312A NZ 626473 B2 NZ626473 B2 NZ 626473B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- compound
- pyrimido
- dihydro
- isoquinolinone
- diseases
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 29
- 200000000018 inflammatory disease Diseases 0.000 title description 2
- 125000005842 heteroatoms Chemical group 0.000 claims description 91
- 229910052760 oxygen Inorganic materials 0.000 claims description 81
- 229910052717 sulfur Inorganic materials 0.000 claims description 80
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 57
- 125000005843 halogen group Chemical group 0.000 claims description 51
- 229910052757 nitrogen Inorganic materials 0.000 claims description 49
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 33
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 25
- 125000002947 alkylene group Chemical group 0.000 claims description 8
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 7
- 125000004450 alkenylene group Chemical group 0.000 claims description 7
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 742
- 201000010099 disease Diseases 0.000 abstract description 85
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- 101700085774 GPR84 Proteins 0.000 abstract description 59
- 206010021972 Inflammatory bowel disease Diseases 0.000 abstract description 42
- 201000009794 idiopathic pulmonary fibrosis Diseases 0.000 abstract description 35
- 230000004968 inflammatory condition Effects 0.000 abstract description 27
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- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 abstract description 25
- 210000002865 immune cell Anatomy 0.000 abstract description 24
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- 125000003118 aryl group Chemical group 0.000 description 54
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- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 14
- IRSFLDGTOHBADP-UHFFFAOYSA-N embelin Chemical compound CCCCCCCCCCCC1=C(O)C(=O)C=C(O)C1=O IRSFLDGTOHBADP-UHFFFAOYSA-N 0.000 description 14
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-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
compound according to Formula (Ia) wherein L1, and G, and R1 are as described herein. The present disclosure relates to compounds that antagonize GPR84, a G-protein-coupled receptor that is involved in inflammatory conditions, and methods for the production of these compounds, pharmaceutical compositions comprising these compounds, and methods for the prevention and/or treatment of inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions by administering a compound of formula (Ia). ositions comprising these compounds, and methods for the prevention and/or treatment of inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions by administering a compound of formula (Ia).
Description
NOVEL DIHYDROPYRIMIDINOISOQUINOLINONES AND PHARMACEUTICAL
COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY
DISORDERS.
FIELD OF THE INVENTION
The present invention relates to novel compounds that antagonize GPR84, a G-protein-coupled
or that is involved in inflammatory conditions.
The present invention also provides methods for the production of these novel compounds,
pharmaceutical compositions sing these compounds, and methods for the prevention and/or treatment
of inflammatory conditions (for e inflammatory bowel es (IBD), rheumatoid arthritis, vasculitis,
lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g.
idiopathic ary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune
diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell
functions by administering a compound of the invention.
BACKGROUND OF THE ION
GPR84 was recently isolated and characterized from human B cells (Wittenberger et al., 2001, J
Mol Biol, 307, 799-813) as the result of an expressed sequence tag data mining strategy, and also using a
degenerate primer reverse transcriptase-polymerase chain reaction (RT-PCR) approach aimed to identify
novel chemokine receptors expressed in neutrophils (Yousefi S et al. 2001 J Leukoc 9, 1045—52).
GPR84 (also known as EX33) ed an orphan GPCR until the identification of medium-chain
FFAs with carbon chain lengths of 9-14 as ligands for this receptor (Wang et al. (2006) J. Biol. Chem.
281:3457-64). GPR84 was bed to be activated by capric acid (C10:0), noic acid (C11:0) and
lauric acid (C12:0) with potencies of 5 uM, 9 uM and 11 uM, respectively. Two small molecules were also
described to have some GPR84 agonist activity: 3,3’ di-indolylmethane (DIM) (Wang et al. (2006) J. Biol.
Chem. 281:3457-64) and embelin ().
GPR84 expression has been shown to be sed in immune cells at least but not limited to
polymorphonuclear leukocytes (PMN), neutrophils, monocytes, T cells, B cells. (Wang et al., 2006, The
Journal of Biological Chemistry, 281, 45, 3457-3464, Yousefi et al., 2001, Journal of yte Biology, 69,
1045-1052, Venkataraman and Kuo, 2005, Immunology s, 101, 144-153, W02007/027661 A2). Higher
levels of GPR84 were measured in neutrophils and eosinophils than in T-cells and B-cells. GPR84 expression
was demonstrated in tissues that may play a role in the propagation of the inflammatory response such as
lung, spleen, bone marrow.
For example, in a recent , Du Bois reported the current status of ies for lung
interstitial es, such as thic pulmonary fibrosis (IPF). There are almost 300 distinct injurious or
inflammatory causes of interstitial lung disease that can result in diffuse lung scarring, and the initial stages
of the IPF pathology are very likely to involve inflammation (Du Bois, 2010, Nat Rev, Drug Discovery, 9,
129), and ation therapies involving nflammatory treatment could be advantageously used.
The expression of GPR84 was highly up-regulated in monocytes/macrophages upon LPS
stimulation (Wang et al., 2006, The Journal of Biological Chemistry, 281, 45, 3457-3464).
GPR84 knock-out (KO) mice are viable and indistinguishable from wild-type littermate controls
(Venkataraman and Kuo, 2005, Immunology Letters, 101, 144-153). The proliferation of T and B cells in
se to various mitogens is reported to be normal in GPR84-deficient mice (Venkataraman and Kuo,
2005, Immunology Letters, 101, 3). T helper 2 (Th2) differentiated T cells from GPR84 KO secreted
higher levels of IL4, IL5, ILl3, the 3 major Th2 cytokines, compared to wild-type littermate controls. In
contrast, the production of the Th1 cytokine, INFy, was r in Th1 differentiated T cells from GPR84 K0
and ype littermate (Venkataraman and Kuo, 2005, Immunology Letters, 101, 144-153).
[0009] In addition, capric acid, undecanoic acid and lauric acid dose ently increased the ion
of interleukin-12 p40 t (IL-12 p40) from .7 murine macrophage-like cells stimulated with
LPS. The pro-inflammatory cytokine IL-12 plays a pivotal role in promoting cell-mediated immunity to
eradicate pathogens by inducing and maintaining T helper 1 (Th1) responses and inhibiting T helper 2 (Th2)
responses. Medium-chain FFAs, through their direct actions on GPR84, may affect Thl/Th2 balance.
[0010] Berry et al. identified a whole-blood 393-gene transcriptional signature for active ulosis
(TB) (Berry et al., 2010, Nature, 466, 973-979). GPR84 was part of this whole-blood 393-gene
transcriptional signature for active TB indicating a potential role for GPR84 in infectious es.
GPR84 expression was also described in microglia, the primary immune effector cells of the
central nervous system (CNS) from myeloid-monocytic origin (Bouchard et al., 2007, Glia, 55:790-800). As
observed in peripheral immune cells, GPR84 expression in microglia was highly inducible under
inflammatory conditions such as TNFa and IL1 treatment but also notably endotoxemia and experimental
autoimmune encephalomyelitis (EAE), suggesting a role in neuro-inflammatory processes. Those results
suggest that GPR84 would be up-regulated in CNS not only during endotoxemia and multiple sclerosis, but
also in all neurological conditions in which TNFa or Ile pro-inflammatory cytokines are produced,
including brain injury, infection, Alzheimer’s disease (AD), Parkinson's disease (PD).
GPR84 expression was also observed in adipocytes and shown to be enhanced by inflammatory
stimuli aki er al., 2012). The results suggest that GPR84 emerges in adipocytes in response to TNFa
from infiltrating macrophages and exacerbates the vicious cycle between adiposity and diabesity, and
ore the inhibition of GPR84 activity might be beneficial for the treatment of endocrine and/or metabolic
diseases.
Therefore, the present invention provides novel compounds, processes for their preparation and
their use in the preparation of a medicament for the treatment of inflammatory conditions (for example
inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e. g. chronic ctive
pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))),
nflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic
es, and/or diseases involving impairment of immune cell functions.
SUMMARY OF THE INVENTION
[0014] The present invention relates to novel dihydropyrimidinoisoquinolinone compounds that
antagonize GPR84, and that are potentially useful for the treatment of inflammatory conditions (for example
inflammatory bowel es (IBD), toid arthritis, vasculitis, lung diseases (e.g. chronic obstructive
pulmonary disease (COPD) and lung interstitial es (e.g. idiopathic pulmonary fibrosis (IPF))),
nflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic
diseases, and/or es involving impairment of immune cell functions.
The present invention also provides methods for the production of these compounds,
pharmaceutical compositions comprising these compounds and s for treating inflammatory conditions
(for e atory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic
obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. thic pulmonary fibrosis
(IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic
diseases, and/or diseases involving impairment of immune cell functions.
Accordingly, in a first aspect of the invention, a compound of the invention is disclosed having a
Formula Ia:
CAN |
wherein
R1 is H, Me, or halo;
L1 is absent or is -O-, -S-, or -NR4a-;
G is
-W-L2-R2, or
-W-L3-R3;
W is C1_4 alkylene, C2_4 alkenylene having one double bond, or C2_4 alkynylene having one triple
bond;
L2 is absent or is -O-;
R2 is
_ H,
- CH; alkyl, optionally tuted with one to three groups independently selected from
O OH,
O halo,
O CN,
C1_6 alkoxy,
C3_7 lkyl,
4-6 membered heterocycloalkyl comprising one to three heteroatoms independently
selected from S, and 0,
-6 membered heteroaryl comprising one to three heteroatoms independently selected
from N, S, and O, and
O phenyl,
- C4_7 lkenyl comprising one double bond,
- 5-7 membered heterocycloalkenyl comprising one double bond, and one to three heteroatoms
independently selected from N, O, and S,
- C3_7 cycloalkyl optionally tuted With one or more independently selected R5 groups,
- 4-10 membered heterocycloalkyl comprising one to two heteroatoms independently selected
from S, and O, optionally substituted with one to three independently selected R5 ,
- 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N,
S, and O, optionally substituted with one to three independently ed R6 groups, or
- C640 aryl optionally substituted with one or more independently selected R6 groups;
L3 is -NR4b-;
- C1_4 alkyl substituted With
0 C640 aryl optionally substituted with one or more independently ed R7 groups, or
0 5-10 membered heteroaryl comprising one to three heteroatoms ndently selected
from N, S, and O, optionally substituted with one or more independently selected R7
groups,
-10 membered heteroaryl comprising one to three heteroatoms independently selected from N,
S, and O, optionally substituted With one or more independently selected R7 groups, or
C640 aryl optionally substituted with one or more independently selected R7 groups;
Each R4&1 and R4b is independently selected from H, C14 alkyl, and C3_7 cycloalkyl;
- 6
R 1soxoorR;
R6 is
OH,
halo,
-N02,
C1_6 alkyl optionally substituted with one to three groups independently selected from halo, and
C1_6 alkoxy optionally substituted with one to three groups independently selected from halo, and
C3_7 cycloalkyl,
-C(=O)OR8,
-C(=O)NR9R1°,
-NHC(=O)-C1_4 alkyl,
-CN,
phenyl,
-O-phenyl,
4-7 membered heterocycloalkyl comprising one to three atoms independently selected
from N, O, and S, or
-6 membered heteroaryl comprising one to three heteroatoms independently selected from N, O,
and S; optionally substituted with one or more indepentently selected C14 alkyl, C1_4 alkoxy, CN,
halo, and —C(=0)0R“;
R7 is C1_4 alkyl, or halo, and
each of R8, R9, R10 and R11 is ndently selected from H and C1_4 alkyl.
In a further aspect, the present ion provides pharmaceutical compositions comprising a
nd of the ion, and a pharmaceutical carrier, excipient or t. Moreover, a compound of the
t invention useful in the pharmaceutical compositions and treatment methods disclosed herein, is
ceutically acceptable as prepared and used. In this aspect of the invention, the pharmaceutical
composition may onally comprise further active ingredients le for use in combination with
a compound of the invention.
[0018 ] In another aspect of the invention, this inventio n provides novel compounds of the
invention for use in therapy.
[0019] In a further aspect of the invention, this invention provides a method of treating a mammal
susceptible to or afflicted with a ion from among those listed herein, and ularly, such
condition as may be associated with aberrant ty of GPR84 and/or aberrant GPR84 expression
and/or aberrant GPR84 distribution, for example inflammatory conditions (for e inflammatory
bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive
pulmonary disease (COPD) and lung titial diseases (e.g. idiopathic pulmonary fibrosis ),
neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic
diseases, and/or diseases involving impairment of immune cell functions, which method comprises
administering a eutically effective amount of a nd of the invention, or one or more of the
pharmaceutical compositions herein described.
[0020] In a further aspect, the present invention provides a compound of the invention for use in
the treatment or prevention of a condition selected from those listed herein, ularly such conditions
as may be associated with aberrant ty of GPR84 and/or aberrant GPR84 expression and/or
aberrant GPR84 distribution expression such as matory conditions (for example inflammatory
bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive
pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))),
neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or lic
diseases, and/or diseases involving ment of immune cell functions.
In additional aspects, this invention provides methods for synthesizing a compound of the
invention, with representative synthetic ols and pathways disclosed herein.
[0022] Accordingly, it is an aspect of this invention to provide a compound of the invention, which
can modify the activity of GPR84 and thus prevent or treat any conditions that may be causally related
thereto.
It is further an aspect of this invention to provide a compound of the invention that can treat
or alleviate conditions or diseases or symptoms of same, such as inflammatory conditions (for example
inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic
obstructive ary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis
(IPF))), neuroinflammatory conditions, infectious diseases, mune diseases, endocrine and/or
metabolic es, and/or diseases involving impairment of immune cell functions, that may be
causally related to the activity and / or sion and/or distribution of GPR84.
[0024] A still further aspect of this invention is to provide pharmaceutical compositions that may
be used in the ent or prevention of a variety of disease states, including the diseases associated
with aberrant activity of GPR84 and/or aberrant GPR84 expression and/or aberrant GPR84 distribution
such as inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid
arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung
interstitial diseases (e.g. idiopathic pulmonary fibrosis ), nflammatory conditions,
infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases
involving impairment of immune cell functions.
Other aspects and advantages will become apparent to those skilled in the art from a
consideration of the ensuing ed description.
] The use of a compound according to any one of the preceding aspects in the manufacture of
a medicament for the treatment or prophylaxis of inflammatory conditions.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0026] The following terms are intended to have the meanings presented therewith below and are
useful in understanding the description and ed scope of the present invention.
When describing the invention, which may include compounds, ceutical
itions containing such nds and methods of using such nds and compositions,
the following terms, if present, have the following gs unless otherwise indicated. It should also
be understood that when bed herein any of the moieties defined forth below may be substituted
with a variety of substituents, and that the respective definitions are intended to include such
substituted moieties within their scope as set out below. Unless otherwise stated, the term 'substituted'
is to be defined as set out below. It should be further understood that the terms 'groups' and 'radicals'
can be considered interchangeable when used herein.
[0028] The articles 'a' and 'an' may be used herein to refer to one or to more than one (i.e. at least
one) of the grammatical objects of the article. By way of e 'an analogue' means one analogue or
more than one analogue.
'Alkyl' means straight or branched aliphatic hydrocarbon having the specified number of
carbon atoms. Particular alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched
means that one or more alkyl groups such as methyl, ethyl or propyl is attached to a linear alkyl chain.
Particular alkyl groups are , ethyl, n-propyl, pyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, nhexyl
, and 1,2-dimethylbutyl. Particular alkyl groups have between 1 and 4 carbon atoms.
ene' refers to divalent alkane radical groups having the number of carbon atoms
specified, in particular 1 to 6 carbon atoms and more particularly 1 to 4 carbon atoms which can be
straight-chained or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene
(-CH 2-CH 2-), the propylene isomers (e.g., -CH2-CH 2-CH 2- and -CH(CH3)-CH 2-) and the like.
'Alkenylene' refers to nt alkene radical groups having the number of carbon atoms and
the number of double bonds specified, in particular 2 to 6 carbon atoms and more particularly 2 to 4
carbon
atoms which can be straight-chained or branched. This term is exemplified by groups such as -CH=CH-, -
CHz-CH=CH-, -C(CH3)=CH-, -C(CH3)=CH-CH2-, -C(CH3)=C(CH3)-, and -CH2-C(CH3)=CH-.
‘Alkynylene’ refers to divalent alkyne l groups having the number of carbon atoms and the
number of triple bonds specified, in particular 2 to 6 carbon atoms and more particularly 2 to 4 carbon atoms
which can be straight-chained or branched. This term is exemplified by groups such as -CEC-, -CH2-CEC-,
and -C(CH3)H-CECH-.
y’ refers to the group O-alkyl, where the alkyl group has the number of carbon atoms
specified. In particular the term refers to the group -O-C1-C6 alkyl. Particular alkoxy groups are methoxy,
ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, toxy, n-pentoxy, n-hexoxy, and 1,2-
dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further
particular alkoxy groups have between 1 and 4 carbon atoms.
‘Amino’ refers to the radical -NH2.
‘Aryl’ refers to a monovalent aromatic arbon group derived by the removal of one
hydrogen atom from a single carbon atom of a parent aromatic ring system. In particular aryl refers to an
aromatic ring structure, mono-cyclic or poly-cyclic that includes the number of ring members ed.
Particular aryl groups have from 6 to 10 ring members. Where the aryl group is a monocyclic ring system it
entially contains 6 carbon atoms. Particularly aryl groups include phenyl, naphthyl, indenyl, and
tetrahydronaphthyl.
‘Carboxy’ refers to the radical -C(O)OH.
[0037] ‘Cycloalkyl’ refers to cyclic non-aromatic hydrocarbyl groups having the number of carbon atoms
ed. Particular cycloalkyl groups have from 3 to 7 carbon atoms. Such cycloalkyl groups e, by
way of example, single ring structures such as cyclopropyl, cyclobutyl, entyl, cyclohexyl, and
cycloheptyl.
‘Cyano’ refers to the radical -CN.
[0039] ‘Halo’ or ‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (1). Particular halo
groups are either fluoro or chloro.
‘Hetero’ when used to describe a compound or a group present on a compound means that one or
more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfiJr
atom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g.
heteroalkyl, cycloalkyl, e. g. heterocycloalkyl, aryl, e.g. heteroaryl, and the like having from 1 to 5, and
particularly from 1 to 3 heteroatoms.
‘Heteroaryl’ means an aromatic ring structure, mono-cyclic or polycyclic, that includes one or
more heteroatoms and the number of ring members specified. ular heteraryl groups have 5 to 10 ring
members, or 5 to 6 ring members. The heteroaryl group can be, for example, a five membered or six
membered monocyclic ring or a bicyclic ure formed from fiJsed five and six membered rings or two
fused six membered rings or, by way of a fithher example, two fiJsed five membered rings. Each ring may
contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen. lly the heteroaryl
ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a
single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The
nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially
non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms
present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrole, furan,
thiophene, ole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, le, isothiazole, pyrazole,
triazole and tetrazole groups. Examples of six membered monocyclic heteroaryl groups e but are not
limited to pyridine, ne, pyridazine, pyrimidine and triazine. Particular examples of bicyclic heteroaryl
groups containing a five membered ring fused to another five membered ring include but are not limited to
imidazothiazole and imidazoimidazole. Particular examples of bicyclic heteroaryl groups containing a six
membered ring fused to a five membered ring include but are not limited to benzfuran, benzthiophene,
benzimidazole, benzoxazole, isobenzoxazole, oxazole, benzthiazole, benzisothiazole, isobenzofuran,
, isoindole, isoindolone, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole,
pyrazolopyrimidine, triazolopyrimidine, benzodioxole and lopyridine groups. Particular examples of
bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline,
isoquinoline, chroman, roman, chromene, omene, chroman, isochroman, benzodioxan,
quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, oline, ine, phthalazine,
naphthyridine and pteridine groups. Particular heteroaryl groups are those d from thiophene, pyrrole,
benzothiophene, benzofiJran, indole, ne, quinoline, imidazole, oxazole and pyrazine.
Examples of representative heteroaryls e the following:
H N N
flN/) [“3
N/ OE:N/ N /®©
[93N\ CE.” CCN CD:N
wherein each Y is ed from >C=O, NH, O and S.
As used herein, the term ‘heterocycloalkyl’ refers to a stable heterocyclic non-aromatic ring
and/or rings containing one or more heteroatoms independently selected from N, O and S, fused o
wherein the group contains the number of ring members specified. Particular heterocycloalkyl groups have
2012/076275
4-10 ring s or 5 to 7 ring members, or 5 to 6 ring members. The heterocycloalkyl group can be, for
example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five
and six membered rings or two fused six membered rings or, by way of a further example, two fused five
membered rings. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and
oxygen. Typically the heterocycloalkyl ring will contain up to 4 heteroatoms, more typically up to 3
heteroatoms, more usually up to 2, for example a single atom. In one embodiment, the heterocycloalkyl
ring contains at least one ring nitrogen atom. A fused heterocyclic ring system may include carbocyclic rings
and need only include one heterocyclic ring. Examples of heterocyclic rings include, but are not limited to,
morpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 1-
pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, pyran (2H-pyran or 4H-pyran),
dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene,
dioxane, tetrahydropyran (e.g. ahydro l), imidazoline, olidinone, oxazoline, thiazoline, 2-
pyrazoline, pyrazolidine, zine, and N—alkyl piperazines such as N—methyl piperazine, Further examples
include thiomorpholine and its S-oxide and S,S-dioxide (particularly thiomorpholine). Still further examples
include azetidine, piperidone, piperazone, and N—alkyl piperidines such as N—methyl piperidine. Particular
examples of cycloalkyl groups are shown in the following rative examples:
Y YVA/ Y/X YE w
[W1 0
Y 1? L? C65
it? Cd/
wherein each W is selected from CH2, NH, O and S; and each Y is ed from NH, O, CO, S02, and S.
‘Hydroxy’ refers to the radical -OH.
[0045] ‘Nitro’ refers to the radical -NOZ.
‘Substituted’ refers to a group in which one or more hydrogen atoms are each independently
replaced with the same or different substituent(s).
‘Thiol’ refers to the group -SH.
‘Thioalkoxy’ refers to the group -SR10 where R10 is an alkyl group with the number of carbon
atoms specified. In particular thioalkoxy groups where R10 is a C1-C6 alkyl. Particular thioalkoxy groups are
thiomethoxy, thioethoxy, n-thiopropoxy, opropoxy, n-thiobutoxy, tert-thiobutoxy, iobutoxy, nthiopentoxy
, n-thiohexoxy, and 1,2-dimethylthiobutoxy. ular thioalkoxy groups are lower thioalkoxy,
i.e. with between 1 and 6 carbon atoms. Further particular thioalkoxy groups have between 1 and 4 carbon
atoms.
As used herein, the term ‘substituted with one or more’ refers to one to four substituents. In one
embodiment it refers to one to three substituents. In further embodiments it refers to one or two substituents.
In a yet further embodiment it refers to one substituent.
One having ry skill in the art of organic sis will recognize that the m number
of heteroatoms in a stable, chemically feasible heterocyclic ring, r it is aromatic or non aromatic, is
determined by the size of the ring, the degree of unsaturation and the valence of the heteroatoms. In general,
a heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically
feasible and .
‘Pharmaceutically acceptable’ means approved or approvable by a regulatory agency of the
Federal or a state government or the corresponding agency in countries other than the United States, or that is
listed in the US. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more
particularly, in humans.
[0052] ‘Pharmaceutically acceptable salt’ refers to a salt of a compound that is pharmaceutically
acceptable and that possesses the desired pharmacological activity of the parent nd. In particular,
such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically,
such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such
as acetic acid, nic acid, hexanoic acid, entanepropionic acid, glycolic acid, pyruvic acid, lactic
acid, malonic acid, ic acid, malic acid, maleic acid, fiimaric acid, tartaric acid, citric acid, c acid,
ydroxybenzoyl) benzoic acid, cinnamic acid, ic acid, esulfonic acid, ethanesulfonic acid,
1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic
acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct
ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic
acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid,
muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent nd either is
replaced by a metal ion, e. g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates
with an organic base such as ethanolamine, nolamine, triethanolamine, N—methylglucamine and the
like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium,
tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non toxic
organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate
and the like. The term ‘pharmaceutically acceptable cation’ refers to an acceptable cationic counter-ion of an
acidic fiJnctional group. Such cations are exemplified by sodium, potassium, calcium, magnesium,
ammonium, tetraalkylammonium cations, and the like.
WO 92791
‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which
a compound of the invention is administered.
‘Prodrugs’ refers to compounds, including derivatives of the compounds of the invention,which
have cleavable groups and become by solvolysis or under physiological ions the compounds of the
invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline
ester derivatives and the like, N—alkylmorpholine esters and the like.
te’ refers to forms of the compound that are associated with a solvent, usually by a
solvolysis reaction. This physical association includes hydrogen bonding. tional solvents include
water, ethanol, acetic acid and the like. The compounds of the invention may be prepared e.g. in crystalline
form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such
as hydrates, and r include both iometric solvates and non-stoichiometric solvates. In certain
instances the solvate will be capable of isolation, for example when one or more solvent molecules are
incorporated in the crystal lattice of the crystalline solid. ‘Solvate’ encompasses both solution-phase and
isolable solvates. Representative solvates include hydrates, ethanolates and olates.
[0056] ‘Subject’ es humans. The terms ‘human’, ‘patient’ and ‘subject’ are used interchangeably
herein.
‘Effective amount’ means the amount of a compound of the invention that, when stered to a
subject for treating a disease, is sufficient to effect such treatment for the e. The “effective amount”
can vary depending on the compound, the disease and its ty, and the age, weight, etc., of the subject to
be treated.
nting’ or ‘prevention’ refers to a reduction in risk of acquiring or developing a disease or
er (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may
be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
The term ‘prophylaxis’ is related to ‘prevention’, and refers to a measure or procedure the purpose
of which is to prevent, rather than to treat or cure a disease. Non-limiting examples of prophylactic measures
may include the stration of vaccines; the administration of low lar weight n to hospital
patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti-malarial
agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk
of contracting malaria is high.
[0060] ‘Treating’ or ment’ of any disease or disorder refers, in one embodiment, to ameliorating the
disease or disorder (i.e., arresting the disease or ng the manifestation, extent or severity of at least one
of the clinical symptoms thereof). In another embodiment ‘treating’ or ‘treatment’ refers to ameliorating at
least one physical parameter, which may not be discernible by the subject. In yet another embodiment,
ing’ or ‘treatment’ refers to ting the disease or disorder, either physically, (e.g., stabilization of a
discernible m), physiologically, (e.g., stabilization of a physical parameter), or both. In a fithher
embodiment, ing” or “treatment” relates to slowing the progression of the disease.
As used herein the term ‘inflammatory condition(s)’ refers to the group of conditions including,
rheumatoid arthritis, osteoarthritis, le idiopathic arthritis, vasculitis, psoriasis, gout, allergic airway
disease (e.g. asthma, rhinitis), inflammatory bowel diseases (e.g. Crohn’s e, ulcerative colitis), and
endotoxin-driven disease states (e.g. complications after bypass surgery or chronic endotoxin states
contributing to e. g. chronic cardiac failure). ularly the term refers to rheumatoid tis, allergic
airway disease (e.g. asthma) and atory bowel diseases.
As used herein, the term ‘infectious es’ refers to bacterial infectious diseases and includes but
is not limited to conditions such as sepsis, septicemia, endotoxemia, systemic inflammatory response
syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving, for example,
Yersinia, Salmonella, dia, Shigella, or enterobacteria s.
As used herein the term ‘autoimmune disease(s)’ refers to the group of diseases including
obstructive airways disease (including conditions such as COPD (Chronic obstructive ary disease)),
psoriasis, asthma (e.g intrinsic asthma, extrinsic , dust asthma, infantile asthma) particularly chronic or
inveterate asthma (for example late asthma and airway hyperreponsiveness), bronchitis, ing bronchial
asthma, systemic lupus erythematosus (SLE), le sclerosis, type I diabetes mellitus and complications
associated ith, atopic eczema (atopic itis), contact dermatitis and further eczematous dermatitis,
vasculitis, inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis), atherosclerosis and
amyotrophic l sclerosis. Particularly the term refers to COPD, asthma, psoriasis, systemic lupus
erythematosis, type I diabetes mellitus, vasculitis and inflammatory bowel disease.
As used herein the term ‘endocrine and/or lic disease(s)’ refers to the group of conditions
involving the body’s over- or under-production of certain hormones, while metabolic disorders affect the
body’s ability to process certain nutrients and vitamins. Endocrine disorders include hypothyroidism,
congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, es of the adrenal
glands (including Cushing’s syndrome and Addison’s e), and ovarian dysfunction (including polycystic
ovary syndrome), among others. Some examples of metabolic disorders include cystic fibrosis,
ketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.
As used herein, the term ‘diseases involving impairment of immune cell functions’ includes
conditions with symptoms such as recurrent and drawn out viral and bacterial infections, and slow recovery.
Other invisible symptoms may be the inability to kill off parasites, yeasts and ial pathogens in the
intestines or throughout the body.
As used herein the term ‘neuroinflammatory conditions’ refers to diseases or disorders
characterized by abrupt neurologic deflcits associated with inflammation, demyelination, and axonal damage,
and includes but is not limited to conditions such as Guillain-Barré syndrome (GBS), multiple sclerosis,
axonal degeneration, autoimmune alomyelitis.
‘Compound(s) of the invention’, and equivalent sions, are meant to e compounds of
the Formula(e) as herein described, which expression includes the pharmaceutically acceptable salts, and the
solvates, e.g., hydrates, and the solvates of the pharmaceutically acceptable salts where the context so
permits. rly, reference to intermediates, whether or not they themselves are claimed, is meant to
embrace their salts, and es, where the context so permits.
When ranges are referred to herein, for example but without limitation, C1_6 alkyl, the citation of a
range should be considered a representation of each member of said range.
[0069] Other derivatives of the compounds of this invention have activity in both their acid and acid
derivative forms, but in the acid ive form often offers advantages of solubility, tissue compatibility, or
delayed release in the mammalian organism (see, Bundgard, H., Design of gs, pp. 7-9, 21-24, Elsevier,
Amsterdam 1985). Prodrugs include acid derivatives well know to practitioners of the art, such as, for
example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction
of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed
ides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant
on the compounds of this ion are particularly useful prodrugs. In some cases it is desirable to prepare
double ester type gs such as xy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particular such
prodrugs are the C1 to Cg alkyl, and substituted or unsubstitutedC6_10 aryl, esters of the compounds of the
ion.
As used herein, the term ‘isotopic variant’ refers to a compound that contains unnatural
proportions of isotopes at one or more of the atoms that constitute such compound For e, an ‘isotopic
t’ of a compound can contain one or more non-radioactive es, such as for example, deuterium (2H
or D), carbon-13 (13C), nitrogen-15 (ISN), or the like. It will be understood that, in a compound where such
isotopic substitution is made, the following atoms, where present, may vary, so that for example, any
hydrogen may be 2H/D, any carbon may be 13C, or any nitrogen may be 15N, and that the presence and
placement of such atoms may be determined within the skill of the art. Likewise, the invention may include
the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting
compounds may be used for drug and/or substrate tissue bution studies. The radioactive isotopes
tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of
incorporation and ready means of detection. r, compounds may be prepared that are substituted with
positron emitting isotopes, such as 11C, 18F, 15O and 13N, and would be useful in Positron Emission
Topography (PET) studies for examining substrate receptor occupancy.
All isotopic variants of the nds provided herein, radioactive or not, are intended to be
encompassed within the scope of the invention.
It is also to be tood that compounds that have the same molecular formula but differ in the
nature or ce of bonding of their atoms or the arrangement of their atoms in space are termed ‘isomers’.
Isomers that differ in the arrangement of their atoms in space are termed ‘stereoisomers’.
isomers that are not mirror images of one another are termed ‘diastereomers’ and those that
are non-superimposable mirror images of each other are termed ‘enantiomers’. When a compound has an
tric , for e, it is bonded to four different groups, a pair of enantiomers is possible. An
enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by
the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane
of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A
chiral compound can exist as either individual enantiomer or as a mixture f. A mixture containing
equal proportions of the enantiomers is called a ‘racemic mixture’.
‘Tautomers’ refer to compounds that are interchangeable forms of a particular compound
structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in
equilibrium through the movement of TE electrons and an atom (usually H). For example, enols and s
are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example
of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with
acid or base.
Tautomeric forms may be relevant to the attainment of the l chemical reactivity and
biological activity of a compound of interest.
[0076] The compounds of the invention may possess one or more asymmetric centers; such compounds
can therefore be produced as dual (R)- or (S)— stereoisomers or as mixtures thereof.
Unless indicated otherwise, the description or naming of a particular compound in the
ication and claims is intended to include both individual enantiomers and mixtures, racemic or
otherwise, thereof. The methods for the ination of stereochemistry and the separation of stereoisomers
are well-known in the art.
It will be appreciated that compounds of the invention may be lized to yield biologically
active metabolites.
THE COMPOUNDS
The present invention relates to novel compounds that antagonize GPR84 and that may be useful
for the ent of inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid
arthritis, vasculitis, lung diseases (e. g. chronic obstructive pulmonary disease (COPD) and lung interstitial
diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases,
autoimmune diseases, endocrine and/or metabolic es, and/or diseases involving impairment of immune
cell functions.
The present invention also provides methods for the tion of the nds ofthe
invention, pharmaceutical itions comprising the compounds of the invention and s for treating
diseases involving inflammatory conditions (for example inflammatory conditions (for e
inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive
pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))),
neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic
diseases, and/or diseases involving impairment of immune cell functions, by administering a compound of
the invention. A compound of the invention is an inhibitor of GPR84.
Accordingly, in a first aspect of the invention, a compound of the invention is disclosed having a
Formula Ia:
CAN |
wherein
R1 is H, Me, or halo;
L1 is absent or is -O-, -S-, or -NR4a-;
G is
-W-L2-R2, or
-W-L3-R3;
W is C1_4 alkylene, C2_4 alkenylene having one double bond, or C2_4 alkynylene having one triple
bond;
L2 is absent or is —O-;
R2 is
_ H,
- CH; alkyl, optionally substituted with one to three groups independently selected from
o OH,
0 halo,
WO 92791
0 CN,
0 C1_6 alkoxy,
o C3_7 cycloalkyl,
o 4-6 membered heterocycloalkyl comprising one to three heteroatoms independently
selected from S, and O,
o 5-6 membered heteroaryl comprising one to three heteroatoms independently selected
from N, S, and O, and
o phenyl,
- C4_7 cycloalkenyl comprising one double bond,
- 5-7 membered heterocycloalkenyl comprising one double bond, and one to three heteroatoms
independently selected from N, O, and S,
- C3_7 lkyl optionally substituted With one or more independently selected R5 groups,
- 4-10 membered heterocycloalkyl comprising one to two heteroatoms independently selected
from S, and O, optionally substituted with one to three independently selected R5 groups,
- 5-10 ed heteroaryl comprising one to three heteroatoms independently selected from N,
S, and O, ally substituted With one to three independently selected R6 groups, or
- C640 aryl optionally tuted with one or more ndently selected R6 groups;
L3 is -NR4b-;
R3 is
- C1_4 alkyl substituted with
0 C640 aryl optionally substituted with one or more independently selected R7 groups, or
0 5-10 membered heteroaryl comprising one to three heteroatoms independently selected
from N, S, and O, optionally substituted with one or more R ndently selected R7
groups,
5-10 membered heteroaryl comprising one to three heteroatoms ndently selected from N,
S, and O, optionally substituted With one or more independently selected R7 groups, or
- C640 aryl optionally substituted with one or more independently selected R7 groups;
Each R4&1 and R4b is independently selected from H, C14 alkyl, and C3_7 cycloalkyl;
R5 is oxo or R6;
R6 is
- OH,
- halo,
- -NOZ,
- C1_6 alkyl ally substituted with one to three groups independently selected from halo, and
OH,
C1_6 alkoxy optionally substituted with one to three groups independently selected from halo, and
C3_7 cycloalkyl,
-C(=O)OR8,
-C(=O)NR9R1°,
-NHC(=O)-C1_4 alkyl,
-CN,
-O-phenyl,
4-7 membered heterocycloalkyl comprising one to three heteroatoms independently selected
from N, O, and S, or
-6 membered heteroaryl comprising one to three heteroatoms independently selected from N, O,
and S; optionally substituted with one or more indepentently selected C14 alkyl, C1_4 alkoxy, CN,
halo, and —C(=0)0R“;
7 is C1_4 alkyl,
or halo; and
each of R8, R9, R10 and R11 is ndently ed from H and C1_4 alkyl.
In a further embodiment, a compound of the invention is disclosed having a Formula lb:
wherein R1, L1 and G are as previously described.
[0083] In yet a fithher embodiment, a compound of the invention is sed having a Formula Ic:
CAN I
L1/G
wherein R1, L1 and G are as previously described.
In one embodiment, the compound of the invention is according to Formula Ia, lb or Ic, wherein
R1 is Me, F, or C1.
In one embodiment, the compound of the ion is according to Formula Ia, lb or Ic, n
R1 is H.
In one embodiment, the compound of the ion is according to Formula IIa, IIb, or Ho:
0 o o
/0 be
E 5/0
N/l N/l N/l
OA\N OA\N OA\N
m—W m—W M—W
1m 1m 1m
wherein L1, and R2 are as decribed previously.
In one embodiment, the compound of the invention is according to Formula IIIa, IIIb, or IIIc:
o o
/0 K/o o/\O
O O
L1WQR qw
Ma nm 1%
wherein L, W, L2, and R2 are as decribed previously.
In one embodiment, the compound of the invention is according to Formula IVa, IVb, or No:
09., Lo
/' 09.,
o N o N
LTW LTW1§R3 /W\ ,R3
L1 L3
Va Nb IVc
wherein L, W, L3, and R3 are as decribed previously.
2012/076275
In one embodiment, the compound of the invention is according to any one of Formulae Ia-IVc,
wherein L1 is absent, or is —O-. In a preferred embodiment, L1 is absent.
In another embodiment, the nd of the ion is according to any one of Formulae Ia-
IVc, wherein L1 is -NR4a-, wherein R4&1 is as described previously. In a preferred embodiment, R4&1 is H, Me,
Et, or cyclopropyl. In a more preferred embodiment, R4&1 is H.
In one embodiment, the compound of the invention is ing to any one of Formulae Ia-Ic, or
IIIa-IVc, wherein W is C14 alkylene. In a preferred ment, W is —CH2-, —CH2-CH2-, —CH2-CH2-
CH(CH3)-, —CH2-CH(-CH2-CH3)-, —CH2-C(CH3)2-, or —CH2-CH2-CH2-. In a more preferred embodiment, W
is —CH2-. In another more preferred embodiment, W is—CHZ-CH2-.
[0092] In one ment, the compound of the invention is according to any one of Formulae Ia-Ic, or
IIIa-IVc, wherein W is C2_4 lene having one double bond. In a preferred embodiment, W is —CH=CH-,
—CH2-CH=CH-, or -CH2-. In a more preferred embodiment, W is -CH=CH-. In another more
preferred embodiment, W is —CH2-CH=CH-.
In one embodiment, the compound of the invention is according to any one of Formulae Ia-Ic, or
IIIa-IVc, wherein W is C2_4 alkynylene having one triple bond. In a preferred embodiment, W is —CEC-, —
CHZ-CEC-, or -CEC-CH2-. In a more preferred embodiment, W is -CEC-. In another more preferred
embodiment, W is —CH2-CEC-.
In one embodiment, the compound of the ion is according to any one of Formulae Ia-Ic, or
IIIa-IIIc, wherein L2 is absent. In another embodiment, L2 is —O-.
[0095] In one embodiment, the compound of the invention is according to any one of Formulae Ia-Ic, or
IIIa-IIIc, wherein L1 is absent or is -O-, W is C1_4 alkylene; and L2 and R2 are as described previously. In a
preferred embodiment, W is -CH2-, -CH2-CH2-, or -CH2-CH2-CH2-. In a more preferred embodiment, W is —
CH2-. In another preferred ment, W is-CHZ-CH2-.
In another embodiment, the compound of the invention is ing to any one of Formulae Ia-Ic,
or IIIa-IIIc, wherein L1 is absent or is —O-, W is C2_4 alkenylene having one double bond; and L2 and R2 are as
described previously. In a preferred embodiment, W is -CH=CH-, -CH2-CH=CH-, or -CH=CH-CH2-. In a
more preferred embodiment, W is -CH=CH-. In another more red embodiment, W is -CH2-CH=CH-.
In yet r embodiment, the nd of the invention is according to any one of Formulae
Ia-Ic, or IIIa-IIIc, wherein L1 is absent, W is C2_4 alkynylene having one triple bond; and L2 and R2 are as
described previously. In a preferred embodiment, W is -CEC-, -CH2-CEC-, or -CEC-CH2-. In a more
preferred embodiment, W is -CEC-. In another more preferred embodiment, W is -CH2-CEC-.
In one embodiment, the compound of the invention is ing to any one of Formulae Ia-Ic, or
IIIa-IIIc, wherein L1 and L2 are absent, W is C14 alkylene; and R2 is as described previously. In a preferred
embodiment, W is -CH2—, -CH2-CH2-, or -CH2-CH2-CH2-. In a more preferred ment, W is -CH2-. In
another more preferred embodiment, W is -CH2-CH2-.
In another embodiment, the compound of the invention is according to any one of Formulae Ia-Ic,
or IIIa-IIIc, wherein L1 and L2 are absent, W is C2_4 alkenylene having one double bond; and R2 is as
described previously. In a red embodiment, W is -CH=CH-, -CH2-CH=CH-, or -CH2-. In a
more preferred embodiment, W is -CH=CH-. In another more preferred embodiment, W is -CH2-CH=CH-.
In yet another embodiment, the compound of the invention is according to any one of Formulae
Ia-Ic, or IIIa-IIIc, wherein L1 and L2 are absent, W is C2_4 alkynylene having one triple bond; and R2 is as
described previously. In a preferred embodiment, W is -CEC-, -CH2-CEC-, or -CEC-CH2-. In a more
preferred embodiment, W is -CEC-. In another more preferred embodiment, W is -CH2—CEC-.
In one embodiment, the compound of the invention is according to any one of Formulae Ia-IIIc,
wherein R2 is H.
In another ment, the compound of the invention is according to any one of ae any
one of Formulae Ia-IIIc, wherein R2 is CH; alkyl. In a preferred embodiment, R2 is Me, Et, n-Pr, i-Pr, i-Bu, or
t-Bu. In a more preferred embodiment, R2 is Me, Et, i-Pr or t—Bu. In a more preferred embodiment, R2 is t-
In one embodiment, the compound of the invention is according to any one of Formulae Ia-IIIc,
wherein R2 is C1_g alkyl substituted with one to three groups selected from OH, halo, CN, C1_6 alkoxy, C3_7
cycloalkyl, 4-6 membered heterocycloalkyl (comprising one to three heteroatoms independently selected
from S, and O), 5-6 membered heteroaryl (comprising one to three atoms independently selected from
N, S, and O), and phenyl. In a red embodiment, R2 is Me, Et, n-Pr, i-Pr, i-Bu, or t—Bu tuted with
one to three groups ed from OH, halo, CN, CM alkoxy, C3_7 cycloalkyl, 4-6 membered heterocycloalkyl
(comprising one to three heteroatoms independently selected from S, and O), 5-6 membered heteroaryl
(comprising one to three heteroatoms independently selected from N, S, and O), and phenyl. In another
red embodiment, is C1_g alkyl substituted with one to three groups ed from OH, F, Cl, CN, -OMe,
-OEt, Oi-Pr, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, ydropyranyl, pyrralolyl, imidazolyl,
triazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and phenyl. In a more preferred embodiment,
R2 is Me, Et, n-Pr, i-Pr, i-Bu, or t-Bu substituted with one to three groups ed from OH, F, Cl, CN, -
OMe, -OEt, -Oz'-Pr, cyclopropyl, utyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrralolyl,
imidazolyl, triazolyl, oxazolyl, lyl, pyridinyl, pyrimidinyl, pyrazinyl and phenyl.
In another embodiment, the compound of the invention is according to any one of Formulae Ia-
IIIc, wherein R2 is CH; alkyl substituted with one group selected from OH, halo, CN, C1_6 alkoxy, C3_7
cycloalkyl, 4-6 membered heterocycloalkyl (comprising one to three heteroatoms independently selected
from S, and O), 5-6 ed heteroaryl (comprising one to three heteroatoms independently selected from
N, S, and O), and phenyl. In a preferred embodiment, R2 is Me, Et, n-Pr, i-Pr, i-Bu, or t—Bu substituted with
one group selected from OH, halo, CN, C1_6 alkoxy, C3_7 cycloalkyl, 4-6 membered heterocycloalkyl
(comprising one to three heteroatoms independently ed from S, and O), 5-6 membered heteroaryl
(comprising one to three heteroatoms ndently selected from N, S, and O), and phenyl. In r
preferred ment, is C1_g alkyl substituted with one group selected from OH, F, Cl, CN, -OMe, -OEt, -
Oi-Pr, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofiJranyl, tetrahydropyranyl, olyl, imidazolyl,
lyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and . In a more preferred embodiment,
R2 is Me, Et, n-Pr, i-Pr, i-Bu, or t-Bu substituted with one group selected from OH, F, Cl, CN, -OMe, -OEt, -
Oi-Pr, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,
pyrralolyl, imidazolyl, triazolyl, oxazolyl, lyl, pyridinyl, pyrimidinyl, pyrazinyl, and phenyl. In a most
preferred embodiment, R2 is -CH2-OH, -C(CH3)2-OH, -CH(OH)CH3, -CH(OH)—C2H5, -CH(OH)-C3H7, -
C(OH)(C2H5)2, -C(OH)H-CH(CH3)2, -C(OH)H-CH2-CH(CH3)2, -C(OH)H-C(CH3)3, -CH2-CN, -CH2-OCH3, -
CH2-CH2-OCH3, -CH(OCH3)-CH3, -C(OCH3)H-CH(CH3)2, -CH2-F, —CH2-CH2-F, -CH2-cyclopropyl, -CH2-
cyclopentyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, or -CH2-tetrahydropyranyl.
In one embodiment, the compound of the invention is according to any one of Formulae Ia-IIIc,
wherein R2 is C4_7 cycloalkenyl comprising one double bond. In a preferred embodiment, R2 is cyclohexenyl.
In one embodiment, the nd of the ion is according to any one of ae Ia-IIIc,
wherein R2 is 5-7 membered heterocycloalkenyl comprising one double bond, and one to three heteroatoms
independently selected from N, O, and S. In a preferred embodiment, R2 is dihydropyranyl.
In one embodiment, the compound of the invention is according to any one of Formulae Ia-IIIc,
wherein R2 is C3_7 cycloalkyl. In a preferred embodiment, R2 is cyclopropyl, cyclobutyl, entyl, or
cyclohexyl. In a more preferred embodiment, R2 is cyclopropyl.
In another embodiment, the compound of the invention is according to any one of Formulae Ia-
IIIc, wherein R2 is C3_7 cycloalkyl substituted with one to three independently selected R5 groups. In a
preferred embodiment, R2 is C34 cycloalkyl substituted with one R5 group. In a more preferred embodiment,
R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R5 group. In
another more prefered embodiment, R2 is C3_7 cycloalkyl substituted with one R5 group, wherein R5 is oxo, or
R6 n R6 is selected from OH, or CM alkyl. In a most prefered embodiment, R2 is cyclopropyl,
utyl, cyclopentyl or cyclohexyl, each of which is substituted with one R5 group, n R5 is oxo, or
R6 wherein R6 is ed from OH, or C1_6 alkyl. In a further most prefered embodiment, R2 is cyclopropyl,
cyclobutyl, cyclopentyl or exyl, each of which is tuted with one R5 group, n R5 is R6, and
R6 is selected from OH.
In one embodiment, the compound of the invention is according to any one of Formulae Ia-IIIc,
wherein R2 is 4-10 membered heterocycloalkyl comprising one to two heteroatoms independently selected
from S, and O. In a preferred embodiment, R2 is oxetanyl, ydrofuranyl, tetrahydropyranyl, or dioxanyl.
2012/076275
In another embodiment, the compound of the ion is according to any one of Formulae Ia-
IIIc, R2 is 4-10 membered heterocycloalkyl comprising one to two heteroatoms independently selected from
S, and O substituted with one to three independently selected R5 groups. In a red ment, R2 is 4-
membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and
Osubstituted with one R5 group. In a more preferred embodiment, R2 is 4-10 membered heterocycloalkyl
comprising one to two heteroatoms independently selected from S, and O substituted with one R5 group,
wherein R5 is selected from oxo, or R6 wherein R6 is selected from OH, and C1_6 alkyl. In another more
red embodiment, R2 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl, each of which is
substituted with one R5 group. In a most red ment, R2 is oxetanyl, tetrahydrofuranyl,
tetrahydropyranyl, or dioxanyl, each of which is substituted with one R5 group, wherein R5 is selected from
oxo, or R6 wherein R6 is selected from OH, and C1_6 alkyl,
In one embodiment, the compound of the invention is according to any one of Formulae Ia-IIIc,
R2 is 5-10 membered heteroaryl comprising one to three atoms independently selected from N, S, and
O. In a preferred embodiment, R2 is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, azolyl,
imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl.
In another embodiment, the nd of the invention is according to any one of Formulae Ia-
IIIc, R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S,
and O, substituted substituted with one to three independently selected R6 groups. In a prefered embodiment,
R2 is 5-10 membered aryl comprising one to three heteroatoms independently selected from N, S, and
O, substituted substituted with one or two independently selected R6 groups. In a more preferred
embodiment, R2 is furanyl, thienyl, oxazolyl, lyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl,
pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, substituted with one or two independently selected R6
groups. In another more preferred embodiment, R2 is 5-10 membered heteroaryl comprising one to three
heteroatoms independently selected from N, S, and O, substituted with one or two ndently selected R6
groups, wherein each R6 is independently selected from OH, halo, C1_6 alkyl, CM alkyl substituted with one
or more halo, CM alkoxy, -CN, C3_7 cycloalkyl 4-7 membered cycloalkyl comprising one to three
heteroatoms independently selected from N, O, and S, and phenyl. In most preferred embodiment, R2 is
furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl,
pyrimidinyl, indanyl, or indazolyl, each of which is substituted with one or two independently selected R6
groups, wherein each R6 is independently selected from OH, halo, C1_6 alkyl, CM alkyl substituted with one
or more halo, CM alkoxy, -CN, C3_7 cycloalkyl 4-7 membered heterocycloalkyl comprising one to three
heteroatoms ndently ed from N, O, and S, and phenyl. In r most preferred embodiment, R2
is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O,
tuted with one or two ndently selected R6 groups, wherein each R6 is independently selected from
OH, F, Cl, Me, Et, Pr, i-Pr, t-Bu, -CF3, -OMe, -OEt, Oi-Pr, -CN, ropyl, pyrrolidinyl, morpholinyl,
WO 92791
piperidinyl, or phenyl. In further most preferred embodiment, R2 is fiJranyl, thienyl, oxazolyl, thiazolyl,
oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, each
of which is substituted with one or two independently selected R6 groups, wherein each R6 is ndently
selected from OH, F, Cl, Me, Et, Pr, i-Pr, t—Bu, -CF3, -OMe, -OEt, -Oz’-Pr, -CN, cyclopropyl, pyrrolidinyl,
morpholinyl, dinyl, and phenyl.
In another embodiment, the compound of the invention is according to any one of Formulae Ia-
IIIc, R2 is C640 aryl. In a preferred embodiment, R2 is phenyl.
In another embodiment, the compound of the invention is according to any one of ae Ia-
IIIc, R2 is €6.10 aryl substituted with one or more independently selected R6 groups. In a prefered
embodiment, R2 is €6.10 aryl substituted with one or two independently ed R6 . In a more
preferred embodiment, R2 is €6.10 aryl substituted with one or two independently selected R6 groups, wherein
each R6 group is selected from halo, CN, CM alkyl, CM alkoxy, or -NHC(=O)-C1_4 alkyl. In another more
preferred embodiment, R2 is €6.10 aryl substituted with one or two independently selected R6 groups, wherein
each R6 group is selected from -C(=O)NR9R1°, and each R9 and R10 is independently selected from from H
and C14 alkyl. In yet another more preferred embodiment, R2 is phenyl substituted with one or two
independently selected R6 groups. In a most preferred embodiment, R2 is phenyl substituted with one or two
independently selected R6 groups, wherein each R6 group is selected from halo, CN, CM alkyl, CM alkoxy,
and -NHC(=O)-C1_4 alkyl. In r most preferred embodiment, R2 is phenyl substituted with one or two
independently selected R6 groups, wherein each R6 group is selected from -C(=O)NR9R1°, and each R9 and
R10 is independently selected from from H and C1_4 alkyl. In a further most preferred embodiment R2 is
phenyl substituted with one or two independently selected R6 groups, wherein each R6 group is ed from
F, Cl, CN, Me, -OMe, -OEt, and -NHC(=O)Me. In another further most preferred embodiment R2 is phenyl
substituted with one or two independently selected R6 groups, wherein each R6 group is selected from -
H2, and -C(=O)NHMe.
[00115] In another embodiment, the compound of the invention is according to any one of ae Ia-Ic,
IVa, IVb or IVc, wherein L3 is -NR4b-, and R4b is as decribed previously. In a preferred embodiment, R4b is
H, Me, Et, or ropyl. In a more preferred embodiment, R4&1 is H.
In another embodiment, the compound of the invention is according to any one of Formulae Ia-Ic,
IVa, IVb or IVc, wherein R3 is C1_4 alkyl substituted with C640 aryl optionally substituted with one or more
independently selected R7 groups, or 5-10 membered heteroaryl comprising one to three heteroatoms
ndently selected from N, S, and O, ally substituted with one or more R independently selected
R7 groups. In a red embodiment, R3 is Me or Et, each of which is tuted with C640 aryl optionally
substituted with one or more independently selected R7 ), or 5-10 membered heteroaryl comprising one
to three atoms independently selected from N, S, and O, optionally substituted with one or more R
independently selected R7 groups. In another preferred embodiment, R3 is C1_4 alkyl substituted with phenyl,
WO 92791
or pyridyl, each of which is optionally substituted with one or more independently selected R7 groups. In a
more preferred embodiment, R3 is C14 alkyl substituted with , or pyridyl. In a more preferred
embodiment, R3 is C1_4 alkyl substituted with phenyl, or pyridyl, each of which is substituted with Me, Et, F,
or Cl. In a most preferred ment, R3 is Me or Et, each of which is substituted with phenyl, or pyridyl.
In a more preferred embodiment, R3 is Me or Et, each of which is substituted with phenyl, or pyridyl, each of
which is substituted with Me, Et, F, or Cl.
In one embodiment, the compound of the invention is according to any one of Formulae Ia-Ic,
IVa, IVb or IVc, wherein R3 is 5-10 membered heteroaryl comprising one to three heteroatoms independently
selected from N, s, and o. In a preferred embodiment, R3 is pyridyl.
[00118] In one embodiment, the compound of the invention is according to any one of Formulae Ia-Ic,
IVa, IVb, or IVc, wherein R3 is 5-10 membered heteroaryl comprising one to three heteroatoms
independently selected from N, S, and O, substituted with one or more independently ed R7 groups,
wherein each R7 group is as described previously. In a preferred embodiment, R3 is pyridyl, substituted with
one or more independently selected R7 groups, wherein each R7 group is as described usly. In another
preferred embodiment, R3 is 5-10 membered heteroaryl sing one to three heteroatoms independently
ed from N, S, and O, substituted with one or more independently selected R7 groups, wherein each R7
group is ed from Me, Et, F, and Cl. In a more preferred embodiment, R3 is l substituted with one
or more independently selected R7 groups, wherein each R7 group is selected from Me, Et, F, and Cl. In a
most preferred embodiment, R3 is pyridyl substituted with one R7 group selected from Me, Et, F, and Cl.
[00119] In one embodiment, the compound of the ion is according to any one of ae Ia-Ic,
IVa, IVb, or IVc, wherein R3 is C640 aryl. In a preferred embodiment, R3 is phenyl.
In one embodiment, the compound of the invention is according to any one of Formulae Ia-Ic,
IVa, IVb, or IVc, wherein R3 is €6.10 aryl substituted with one or more independently selected R7 groups,
wherein each R7 group is as described previously. In a preferred embodiment, R3 is , substituted with
one or more independently selected R7 groups, wherein each R7 group is as described previously. In another
red embodiment, R3 is C640 aryl substituted with one or more independently selected R7 groups,
n each R7 group is selected from Me, Et, F, and Cl. In a more preferred embodiment, R3 is phenyl
substituted with one or more independently selected R7 groups, wherein each R7 group is ed from Me,
Et, F, and Cl. In a most preferred embodiment, R3 is phenyl tuted with one R7 group selected from Me,
Et, F, and Cl.
In one embodiment, the compound of the invention is according to Formula Va, Vb, Vc or Vd:
0/} ofi ofi ofi
u" Y F’ Y
N/ N/ N/ N/
AN I CAN I CAN I CAN I
§ R2 o/\R2 R2
Va Vb . Vc or Vd
wherein R2 is as described previously.
In a further embodiment, the compound of the invention is not according to a Va, Vb, Vc
or Vd.
[00123] In another embodiment, the compound of the invention is according to Formula VIa, VIb, VIc or
00. 000 05., co
/ /
o/\R2 R2
Vwherein R2is as described usly. Vlc or Vld
In a further embodiment, the compound of the invention is not according to Formula VIa, VIb,
VIc or VId.
In another embodiment, the compound of the invention is according to Formula VIIa, VIIb, VIIc
or VIId:
ofi ofi ofi 3
O O 0
CAN —Z
R2 OAR R2
Vlla Vllb VIIC Vlld
wherein R2 is as described usly.
[00126] In one embodiment, the compound of the invention is according to Formula Va, Vb, VIa, VIb,
VIIa, or VIIb,wherein R2 is C3_7 cycloalkyl. In a preferred embodiment, R2 is cyclopropyl, cyclobutyl,
cyclopentyl, or cyclohexyl. In a more red embodiment, R2 is cyclopropyl.
In one ment, the compound of the invention is according to Formula Va, Vb, VIa, VIb,
VIIa, or VIIb, wherein R2 is not C3_7 cycloalkyl. In a preferred embodiment, R2 is not cyclopropyl,
cyclobutyl, cyclopentyl, or cyclohexyl. In a more preferred embodiment, R2 is not cyclopropyl.
In another embodiment, the compound of the invention is according to a Va, Vb, VIa, VIb,
VIIa, or VIIb, wherein R2 is C3_7 cycloalkyl substituted with one to three independently ed R5 groups.
In a preferred embodiment, R2 is C3_7 cycloalkyl substituted with one R5 group. In a more preferred
ment, R2 is cyclopropyl, utyl, cyclopentyl or cyclohexyl, each of which is tuted with one
R5 group. In another more prefered embodiment, R2 is C3_7 cycloalkyl substituted with one R5 group, wherein
R5 is oxo, or R6 n R6 is selected from OH, or C1_6 alkyl. In a most prefered embodiment, R2 is
ropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R5 group, wherein
R5 is oxo, or R6 wherein R6 is selected from OH, and C1_6 alkyl. In a further most prefered ment, R2 is
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one R5 group, wherein
R5 is OH.
In another embodiment, the compound of the ion is according to Formula Va, Vb, VIa, VIb,
VIIa, or VIIb, wherein R2 is not C34 cycloalkyl substituted with one to three independently selected R5
groups. In a preferred ment, R2 is not C3_7 cycloalkyl tuted with one R5 group. In a more
preferred embodiment, R2 is not cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is
substituted with one R5 group. In another more prefered embodiment, R2 is not C3_7 cycloalkyl substituted
with one R5 group, wherein R5 is oxo, or R6 wherein R6 is selected from OH, and CM alkyl. In a most
prefered embodiment, R2 is not cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is
substituted with one R5 group, wherein R5 is oxo, or R6 wherein R6 is selected from OH, and C1_6 alkyl. In a
r most prefered embodiment, R2 is not cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of
which is substituted with one R5 group, wherein R5 is OH.
In one embodiment, the compound of the invention is according to Formula Vc, Vd, VIc, VId,
VIIc or VIId, wherein R2 is 5-10 membered aryl comprising one to three heteroatoms independently
selected from N, S, and O. In a preferred embodiment, R2 is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl,
thiadiazolyl, imidazolyl, lyl, nyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl.
In one embodiment, the compound of the invention is ing to Formula Vc, Vd, VIc, VId,
VIIc or VIId, wherein R2 is not 5-10 membered heteroaryl comprising one to three heteroatoms
independently selected from N, S, and O. In a preferred embodiment, R2 is not furanyl, l, oxazolyl,
thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or
indazolyl.
In another embodiment, the compound of the invention is according to Formula Vc, Vd, VIc, VId,
VIIc or VIId, wherein R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently
selected from N, S, and O, substituted with one to three independently selected R6 groups. In a prefered
embodiment, R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected
from N, S, and O, tuted with one or two independently selected R6 groups. In a more preferred
embodiment, R2 is fiJranyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl,
pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, substituted with one or two independently ed R6
. In another more preferred embodiment, R2 is 5-10 membered heteroaryl comprising one to three
heteroatoms independently selected from N, S, and O, substituted with one or two independently selected R6
groups, wherein each R6 is independently selected from OH, halo, C1_6 alkyl, CM alkyl substituted with one
or more halo, CM alkoxy, -CN, C3_7 cycloalkyl 4-7 membered heterocycloalkyl comprising one to three
heteroatoms independently ed from N, O, and S, and phenyl. In a most preferred embodiment, R2 is
furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl,
pyrimidinyl, indanyl, or indazolyl, each of which is tuted with one or two independently selected R6
groups, wherein each R6 is independently ed from OH, halo, C1_6 alkyl, CM alkyl substituted with one
or more halo, CM alkoxy, -CN, C3_7 cycloalkyl, 4-7 membered heterocycloalkyl comprising one to three
atoms independently selected from N, O, and S, and . In another most preferred ment, R2
is 5-10 membered aryl comprising one to three heteroatoms independently selected from N, S, and O,
tuted with one or two independently selected R6 groups, wherein each R6 is independently selected from
OH, F, Cl, Me, Et, Pr, i-Pr, t-Bu, -CF3, -OMe, -OEt, Oi-Pr, -CN, cyclopropyl, pyrrolidinyl, morpholinyl,
piperidinyl, and phenyl. In a r most preferred embodiment, R2 is l, l, oxazolyl, thiazolyl,
oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, each
of which is substituted with one or two independently selected R6 groups, wherein each R6 is independently
selected from OH, F, Cl, Me, Et, Pr, i-Pr, t—Bu, -CF3, -OMe, -OEt, -Oz'-Pr, -CN, cyclopropyl, pyrrolidinyl,
linyl, piperidinyl, and phenyl.
In another embodiment, the compound of the invention is according to Formula Vc, Vd, VIc, VId,
VIIc or VIId, wherein R2 is not 5-10 membered heteroaryl comprising one to three heteroatoms
independently selected from N, S, and O, substituted with one to three independently selected R6 groups. In a
prefered embodiment, R2 is not 5-10 membered heteroaryl comprising one to three heteroatoms
independently ed from N, S, and O, substituted with one or two independently selected R6 groups. In a
more preferred embodiment, R2 is not furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl,
imidazolyl, lyl, pyridinyl, nyl, pyrimidinyl, indanyl, or indazolyl, substituted with one or two
ndently selected R6 groups. In another more preferred ment, R2 is not 5-10 membered
heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, substituted with one
or two independently selected R6 groups, wherein each R6 is independently selected from OH, halo, CM
alkyl, C1_6 alkyl substituted with one or more halo, C1_6 alkoxy, -CN, C3_7 cycloalkyl 4-7 membered
heterocycloalkyl sing one to three heteroatoms independently selected from N, O, and S, and phenyl.
In a most preferred embodiment, R2 is not furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl,
imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, each of which is substituted
with one or two independently selected R6 groups, wherein each R6 is ndently selected from OH, halo,
C1_6 alkyl, C1_6 alkyl substituted with one or more halo, CM alkoxy, -CN, C3_7 cycloalkyl 4-7 membered
heterocycloalkyl comprising one to three heteroatoms independently ed from N, O, and S, and phenyl.
In r most preferred embodiment, R2 is not 5-10 membered heteroaryl comprising one to three
heteroatoms independently selected from N, S, and O, substituted with one or two independently ed R6
groups, wherein each R6 is ndently selected from OH, F, Cl, Me, Et, Pr, i-Pr, z-Bu, -CF3, -OMe, -OEt,
Oi-Pr, -CN, ropyl, pyrrolidinyl, morpholinyl, piperidinyl, and phenyl. In a further most preferred
embodiment, R2 is not furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, olyl, triazolyl,
pyridinyl, pyrazinyl, pyrimidinyl, indanyl, or indazolyl, each of which is substituted with one or two
independently selected R6 groups, wherein each R6 is independently selected from OH, F, Cl, Me, Et, Pr, i-Pr,
Z-Bu, -CF3, -OMe, -OEt, -Oz'—Pr, -CN, cyclopropyl, pyrrolidinyl, morpholinyl, piperidinyl, and phenyl.
In another embodiment, the nd of the invention is according to Formula Vc, Vd, VIc, VId,
VIIc or VIId, wherein R2 is C640 aryl. In a preferred embodiment, R2 is phenyl.
] In another embodiment, the compound of the invention is according to Formula Vc, Vd, VIc or
VId, wherein R2 is not C640 aryl. In a preferred ment, R2 is not phenyl.
] In another embodiment, the compound of the invention is ing to Formula Vc, Vd, VIc, VId,
VIIc or VIId, wherein R2 is €6.10 aryl substituted with one or more independently selected R6 groups. In a
prefered embodiment, R2 is €6.10 aryl substituted with one or two independently selected R6 groups. In a
more preferred embodiment, R2 is €6.10 aryl substituted with one or two independently selected R6 groups,
wherein each R6 group is selected from halo, CN, C1_6 alkyl, CM alkoxy, and -NHC(=O)-C1_4 alkyl. In
another more preferred embodiment, R2 is C640 aryl substituted with one or two independently selected R6
groups, wherein each R6 group is selected from -C(=O)NR9R1°, and each R9 and R10 is independently selected
from from H and C1_4 alkyl. In another more preferred embodiment, R2 is phenyl substituted with one or two
independently selected R6 groups. In a most preferred embodiment, R2 is phenyl substituted with one or two
independently selected R6 groups, wherein each R6 group is selected from halo, CN, CM alkyl, CM alkoxy,
and O)-C1_4 alkyl. In another most preferred embodiment, R2 is phenyl tuted with one or two
independently selected R6 groups, n each R6 group is selected from -C(=O)NR9R1°, and each R9 and
R10 is independently selected from from H and C1_4 alkyl. In a further most preferred ment R2 is
phenyl substituted with one or two independently selected R6 groups, wherein each R6 group is ed from
F, Cl, CN, Me, -OMe, -OEt, - and -NHC(=O)Me. In a further most preferred embodiment R2 is phenyl
substituted with one or two independently selected R6 groups, wherein each R6 group is selected from
C(=O)NH2, and -C(=O)NHMe.
In another embodiment, the compound of the ion is ing to Formula Vc, Vd, VIc, VId,
VIIc or VIId, wherein R2 is not C640 aryl substituted with one or more independently selected R6 groups. In a
prefered embodiment, R2 is not €6.10 aryl substituted with one or two independently ed R6 groups. In a
more preferred ment, R2 is not €6.10 aryl substituted with one or two independently selected R6 groups,
wherein each R6 group is selected from halo, CN, C1_6 alkyl, CM alkoxy, and -NHC(=O)-C1_4 alkyl. In
another more preferred embodiment, R2 is not C640 aryl substituted with one or two independently selected
R6 groups, n each R6 group is selected from -C(=O)NR9R10, and each R9 and R10 is independently
ed from from H and C1_4 alkyl. In another more preferred embodiment, R2 is not phenyl substituted
with one or two independently ed R6 groups. In a most preferred embodiment, R2 is not phenyl
substituted with one or two independently selected R6 groups, n each R6 group is selected from halo,
CN, CM alkyl, CM alkoxy, and -NHC(=O)-C1_4 alkyl, In another most preferred ment, R2 is not
phenyl substituted with one or two ndently selected R6 groups, wherein each R6 group is selected from
NR9R10, and each R9 and R10 is independently selected from from H and C1_4 alkyl, In a further most
preferred embodiment R2 is not phenyl substituted with one or two independently selected R6 groups, wherein
each R6 group is selected from F, Cl, CN, Me, -OMe, -OEt, - and -NHC(=O)Me. In a further most preferred
embodiment R2 is not phenyl substituted with one or two independently selected R6 groups, wherein each R6
group is selected from C(=O)NH2, and -C(=O)NHMe.
In one embodiment, the compound of the invention is selected from:
9 -Allyloxy([1,4]dioxanylmethoxy)—6,7-dihydro-pyrimido[6,1-a]isoquinolinone,
2-([1 ,4]Dioxanylmethoxy)-9 -pyridin-3 -yl-6,7-dihydro-pyrimido[6,1-a]isoquinolinone,
2-([1 xanylmethoxy)-9 -pyridinyl-6,7-dihydro-pyrimido[6,1-a]isoquinolinone,
2-[2-([1,4]Dioxanylmethoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolinyl]-benzonitrile,
3 -[2-([1,4]Dioxanylmethoxy)—4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolinyl]-benzonitrile,
4-[2-([1,4]Dioxanylmethoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolinyl]-benzonitrile,
[2-([1,4]Dioxan-Z-ylmethoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolinyloxy]-acetonitrile,
2-([1,4]Dioxanylmethoxy)(oxazolylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolinone,
2-([1 ,4]Dioxanylmethoxy)-9 -(pyridinylmethoxy)—6,7-dihydro-pyrimido[6, 1 -a]isoquinolinone,
9 -(3 ,5 -Dichloro-phenyl)([1,4]dioxanylmethoxy)-6,7 -dihydro-pyrimido [6,1 -a]isoquinolinone,
9 -Benzofuranyl([1,4]dioxanylmethoxy)-6,7 -dihydro-pyrimido [6,1 -a]isoquinolinone,
2-[2-([1,4]Dioxanylmethoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolinyl]-indolecarboxylic
acid tert-butyl ester,
2-([1 ,4]Dioxanylmethoxy)-9 -(1H-indolyl)-6,7 -dihydro-pyrimido[6,1 -a]isoquinolinone,
2-([1 ,4]Dioxanylmethoxy)-9 -(6-methoxy-pyridin-3 -yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolinone,
2-([1,4]Dioxanylmethoxy)(6-trifluoromethyl-pyridinyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin
one,
2-([1 ,4]Dioxanylmethoxy)-9 -(3 -methyl-3H-imidazolylethynyl)-6,7-dihydro-pyrimido[6,1-
a]isoquinolinone,
9 -(5 -tert-Buty1— [1 ,2 ,4]oxadiazol-3 -y11nethoxy)([1 ,4]dioxany1methoxy)-6,7-dihydro-pyrimido[6,1-
a]isoquinolinone,
-[2-([1,4]Dioxany1methoxy)—4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinoliny1]-pyridine
carboxylic acid methylamide,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -pentyny1-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone,
2-([1 4,]Dioxany1methoxy)(2-pyridiny1-ethy1)-6,7 ro-pyrimido[6, 1 a—]isoquinolinone,
2-([1,4]Dioxany1methoxy)(2--pyrazin-y1-ethy1)-6,7 -dihydro-pyrimido[6, 1 a—]isoquinolinone,
2-([1,4]Dioxany1methoxy)(1H-indol-5 --y1)6,7 -dihydro-pyrimido[6, 1 a—]isoquinolinone,
2-([1,4]Dioxany1methoxy)(2-methoxy-pheny1)-6,7 -dihydro-pyrimido[6, 1 a—]isoquinolinone,
2-([1,4]Dioxany1methoxy)(5 m—e-thoxypyridiny1)-6,7-dihydro-pyrimido[6, 1 a—]isoquinolinone,
2-([1,4]Dioxany1methoxy)(1H-indazol—5 -yl)-6,7 -dihydro-pyrimido[6, 1 a—]isoquinolinone,
4]Dioxany1methoxy) 9 (4 methoxy pheny1)-6 7 dihydro pyrimido[6 1 a]isoquinolin 4 one
3- [2-([1,4]Dioxany1methoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinoliny1]-benzamide,
- [2-([1 4,]Dioxany1methoxy)—4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinoliny1]fluoro-
benzamide,
N— {3 -[2-([1,4]Dioxany1methoxy)—4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinoliny1]-pheny1}-
acetamide,
9 -Cyclopropy1ethyny1—2-( [1 ,4]dioxany1methoxy)-6 ,7-dihydro-pyrimido [6 ,1 -a] isoquinolinone,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(1 -hydroxy-cyclopentylethynyl) -6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolin-4 -
one,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -pyrimidin-5 -y1-6,7-dihydro-pyrimido[6,1-a]isoquinolinone,
9 -Cyclohexeny1([1,4]dioxany1methoxy)—6,7-dihydro-pyrimido[6,1-a]isoquinolinone,
2 -( [1 ,4 ny1methoxy)-9 -(1-methy1—1H-indol-5 -y1)-6,7-dihydro-pyrimido [6 1 -a] isoquinolinone,
2 -( [1 ,4 ny1methoxy)-9 -(6-methy1—pyridin-3 -y1)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -pyridiny1ethyny1-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone,
2 -( [1 ,4 ny1methoxy)-9 -(3 -methoxy-propyny1)-6,7-dihydro-pyrimido [6, 1 -a] isoquinolinone,
-[2-([1,4]Dioxany1methoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9 -y1] -pentynenitrile,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(3 -hydroxy-propyny1)—6,7-dihydro-pyrimido[6,1-a]isoquinolinone,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(4-methoxy-pheny1ethyny1)-6 ,7 -dihydro-pyrimido [6 ,1 quinolinone,
2 -( [1 ,4 ny1methoxy)-9 -pyridin-3 -y1ethyny1-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone,
4-[2-([1,4]Dioxany1methoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9 -y1] -N-methy1—
benzamide,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(3 xy-pheny1)-6,7 -dihydro-pyrimido [6, 1 -a]isoquinolinone,
9 -(2-Chloro-pheny1)([1,4]dioxany11nethoxy)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(4-hydroxy-but-1 -yny1)-6 ,7-dihydro-pyrimido [6 ,1 -a] isoquinolinone,
9 -(1,5 -Dimethy1—1H-pyrazol—3 -y1methoxy)([1,4]dioxany1methoxy)-6 ,7 -dihydro-pyrimido [6 ,1 -
a]isoquinolinone,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(1-methy1—1H-pyrazol-3 thoxy)—6,7 -dihydro-pyrimido[6,1-
a]isoquinolinone,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(3 -methy1—[1,2,4]oxadiazol-5 -y1methoxy)-6,7-dihydro-pyrimido[6,1-
uinolinone,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(4-morpholiny1-pheny1)—6,7-dihydro-pyrimido [6, 1 -a]isoquinolinone,
3 -[2-([1,4]Dioxany1methoxy)oxo-6,7-dihydro-4H-pyrimido [6, 1 -a] isoquinolin-9 -y1] fluoro-
benzamide,
3 -[2-([1,4]Dioxany1methoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9 -y1] -5 -fluoro-
ide,
9 -(3 ,3 -Dimethy1—butyny1)([1,4]dioxany1methoxy)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -pyridiny1ethyny1—6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(3 -methy1—isoxazol-5 -y1methoxy)-6,7-dihydro-pyrimido [6, 1 -a] isoquinolin
one,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(3 -hydroxy-3 -methy1—but6,7-dihydro-pyrimido [6, 1 -a] isoquinolin
one,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(2-methoxy-pyridin-3 -y1)-6,7-dihydro-pyrimido [6 ,1 -a] isoquinolinone,
2 -( [1 ,4 ]Dioxany1methoxy)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone,
9 -(3 ,6-Dihydro-2H-pyran-4 -y1)([1,4]dioxany1methoxy)—6,7-dihydro-pyrimido[6,1-a]isoquinolinone,
-[2-([1,4]Dioxany1methoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9 -y1] -pyridine
carbonitrile,
2 -( [1 ,4 ]Dioxany1methoxy)-9 opropoxy-pyridin-3 -y1)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(6-ethoxy-pyridin-3 -y1)-6 ,7-dihydro-pyrimido [6 1 -a] isoquinolinone,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(6-morpholiny1-pyridin-3 -y1)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolin
one,
9 -(2,3 -Dimethoxy—pheny1)([1,4]dioxany11nethoxy)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone,
9 -(3 -Chloromethoxy-pyridiny1)([1,4]dioxany1methoxy)—6,7-dihydro-pyrimido[6,1-a]isoquinolin-
4-one,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(2-methy1—pyridin-4 -y1)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone,
3 -[2-([1,4]Dioxany1methoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9 -y1] -isonicotinonitri1e,
9 -(2,5 -Dimethoxy—pheny1)([1,4]dioxany11nethoxy)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone,
2-([1,4]Dioxany1methoxy)-9 -(3 ,4,5 rahydro-2H- [1 ,2']bipyridiny1—5 6 ydro-pyrimido [6 ,1 -
a]isoquinolinone,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(2-ethoxy-pyridin-3 -y1)-6 ,7-dihydro-pyrimido [6 1 -a] isoquinolinone,
9 -(2,6-Dimethoxy—pyridin-3 -y1)-2 -( [1 ,4]dioxany1methoxy)-6,7-dihydro-pyrimido [6, 1 -a] isoquinolinone,
4-[2-([1,4]Dioxany1methoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-9 -y1] -nicotinonitri1e,
9 -tert-Butoxymethy1—2-([1,4]dioxany1methoxy)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(2-pyrrolidiny1-pyridin-3 -y1)-6,7-dihydro-pyrimido [6, 1 -a] isoquinolin
one,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(6-pyrrolidiny1-pyridin-3 -y1)-6,7-dihydro-pyrimido [6, 1 -a] isoquinolin
one,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(5 -pheny1-oxazoly1methoxy)-6 ,7-dihydro-pyrimido [6 ,1 -a] isoquinolin
one,
9 -(5 Buty1—oxazol—2-y1methoxy)—2-([1,4]dioxany11nethoxy)-6 ,7 ro-pyrimido [6 ,1 -a]isoquinolin-4 -
one,
9 -(5 -Cyclopropy1—[1,2,4]oxadiazol-3 -y1methoxy)([1,4]dioxany1methoxy)-6 ,7 -dihydro-pyrimido [6 ,1 -
a]isoquinolinone,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(5 -ethy1-[1,2,4]oxadiazol-3 -y1methoxy)-6,7-dihydro-pyrimido[6,1-
a]isoquinolinone,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(5 -methy1—[1,2,4]oxadiazol-3 -y1methoxy)-6,7-dihydro-pyrimido[6,1-
a]isoquinolinone,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(5 -isopropy1— [ 1 ,2,4] oxadiaz01-3 -y1methoxy)-6 ,7 ro-pyrimido [6 ,1 -
a]isoquinolinone,
9 pentylethyny1( [1 ,4]dioxany1methoxy)-6,7-dihydro-pyrimido [6, 1 -a] isoquinolinone,
9 -Cyclohexy1ethyny1—2 -([1 xany1methoxy)—6,7-dihydro-pyrimido [6, 1 -a]isoquinolinone,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(3 -methy1—butyny1)-6,7 ro-pyrimido [6,1 -a]isoquinolinone,
2 -( [1 ,4 ny1methoxy)-9 -hexyny1-6,7-dihydro-pyrimido [6, 1 -a] isoquinolinone,
9 - [3 -(B enzyl-methyl-amino)-prop-1 -yny1] -2 -( [1 ,4]dioxany1methoxy)-6,7-dihydro-pyrimido [6, 1 -
a]isoquinolinone,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(3 -hydroxy-5 -methy1—hex-1 -yny1) -6 ,7-dihydro-pyrimido [6 ,1 -a] isoquinolin
one,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(3 -hydroxy-but-1 -yny1)-6 ,7-dihydro-pyrimido [6 ,1 -a] isoquinolinone,
9 -Cyclopropy1—2-([1,4]dioxany11nethoxy)—6,7 -dihydro-pyrimido[6,1-a]isoquinolinone,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(3 -hydroxy-pentyny1)-6,7-dihydro-pyrimido[6,1-a]isoquinolinone,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(3 -hydroxymethy1—pentyny1)-6,7 ro-pyrimido [6,1 -a]isoquinolin-
4-one,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -(3 -ethy1-3 -hydroxy—pentyny1)-6,7-dihydro-pyrimido [6, 1 -a]isoquinolin-4 -
one,
WO 92791
2 -( [1 ,4 ]Di0xany1meth0xy)-9 -(3 -hydr0xy-3 -pheny1—butyny1)-6,7-dihydr0-pyrimid0 [6, 1 -a] is0quin01in
one,
9 -(3 -Benzylamino-prop -1 -yny1) -2 -( [1 ,4]di0xany1meth0xy)-6,7-dihydr0-pyrimid0 [6, 1 -a] n01in0ne,
2 -( [1 ,4 ]Di0xany1meth0xy)-9 -[(fiirany1methy1)-amin0] -6 ,7-dihydr0-pyrimid0 [6 ,1 -a] n01in0ne,
2 -( [1 ,4 ]Di0xany1meth0xy)-9 -(1 -ethy1— 1 H-pyraz01y1)-6 ,7 -dihydr0-pyrimid0 [6 ,1 -a]is0quin01in-4 -0ne,
2 -( [1 ,4 ]Di0xany1meth0xy)-9 -[1-(3 -methy1-buty1)-1H-pyraz01-4 -y1] -6,7-dihydr0-pyrimid0[6,1-
a]is0quin01in0ne,
2 -( [1 ,4 ]Di0xany1meth0xy)-9 -(5 -methyl-furany1) -6 ,7 -dihydr0-pyrimid0 [6 ,1 -a]is0quin01in0ne,
2 -( [1 ,4 ]Di0xany1meth0xy)-9 -(3 -hydr0xy-hex-1 -yny1)-6 ,7 -dihydr0-pyrimid0 [6 ,1 -a]is0quin01in0ne,
9 -(3 ,5 -Dimethy1— 1 z01y1)( [1 xany1meth0xy)-6 ,7-dihydr0-pyrimid0 [6 1 -a] is0quin01in
one,
2 -( [1 ,4 ]Di0xany1meth0xy)-9 -(1H-pyraz01—4-y1)-6 ,7 -dihydr0-pyrimid0 [6 ,1 -a]is0quin01in0ne,
2 -( [1 ,4 ]Di0xany1meth0xy)-9 -(1-pr0py1—1H-pyraz01—4 -y1)-6,7-dihydr0-pyrimid0 [6, 1 -a] is0quin01in0ne,
2 - [2-((R)-1 -[1,4]Dioxany1meth0xy)—4-0X0-6,7-dihydr0-4H-pyrimid0 [6, 1 -a] is0quin01in-9 -y1] -benzonitrile,
2-[2-((S)[1,4]Dioxany1meth0xy)—4-0x0-6,7-dihydr0-4H-pyrimid0[6,1-a]is0quin01iny1]-benz0nitrile,
9 -(5 -Cyclopr0py1—[1,2,4]0xadiaz01—3 -y1meth0xy)—2-((R)[1,4]di0xany1meth0xy)-6 ,7 -dihydr0-
pyrimido [6 ,1 -a]is0quin01in0ne,
2 -( [1 ,4 ]Di0xany1meth0xy)-9 -ethyny1—6 ,7 -dihydr0-pyrimid0 [6 ,1 quin01in0ne,
2 -( [1 ,4 ]Di0xany1meth0xy)-9 idinylethyny1-6,7-dihydr0-pyrimid0 [6, 1 -a]is0quin01in0ne,
2 -( [1 ,4 ]Di0xany1meth0xy)-9 -(3 -pheny1amin0-pr0p-1 -yny1)-6 ,7-dihydr0-pyrimid0 [6 ,1 -a] is0quin01in0ne,
2 -( [1 ,4 ]Di0xany1meth0xy)-9 -(3 -hydr0xy-3 -pyridin-3 -y1-pr0p -1 -yny1) -6 ,7 r0-pyrimid0 [6 ,1 -
a]is0quin01in0ne,
9 -Cyclopentyloxymethyl([1 ,4]dioxany1meth0xy)—6,7-dihydr0-pyrimid0 [6, 1 -a]is0quin01in0ne,
2 -( [1 ,4 ]Di0xany1meth0xy)-9 -(3 -meth0xymethy1—p entyny1)-6,7-dihydr0-pyrimid0 [6, 1 quin01in-
4-0ne,
9 -Cyclopr0pylethyny1((R)[1,4]di0xany1meth0xy)-6 ,7 -dihydr0-pyrimid0 [6 ,1 quin01in0ne,
2-((S) [1 ,4]Di0xany1meth0xy)-9 -(3 1-but-1 -yny1)-6 ,7 -dihydr0-pyrimid0 [6 ,1 -a]is0quin01in0ne,
2 -( [1 ,4 ]Di0xany1meth0xy)-9 -(3 -imidaz01-1 -y1-pr0p -1 -yny1)-6 ,7 -dihydr0-pyrimid0 [6 ,1 -a]is0quin01in-4 -
one,
9 -(2-Cyclopropyl-ethy1)((R)[1,4]di0xany1meth0xy)-6 ,7 -dihydr0-pyrimid0 [6 ,1 -a]is0quin01in0ne,
9 -Cyclopentyloxymethyl((R)-1 -[1 ,4]dioxany1meth0xy)—6,7-dihydr0-pyrimid0 [6, 1 -a]is0quin01in0ne,
2 -( [1 ,4 ]Di0xany1meth0xy)-9 -(3 -hydr0xy-3 -pyridin-3 -y1-pr0py1)—6,7 -dihydr0-pyrimid0 [6, 1 -a]is0quin01in-
4-0ne,
9 -A11y10xy((R)[1,4]dioxany1meth0xy)-6,7-dihydr0-pyrimid0[6,1-a]is0quin01in0ne,
9 -A11y10xy((S)[1,4]dioxany1meth0xy)—6,7-dihydr0-pyrimid0[6,1-a]is0quin01in0ne,
2-((R) [1 ,4 ]Dioxan-2 -y11nethoxy)-9 -(tetrahydro-pyranyloxymethy1) -6 ,7 -dihydro-pyrimido [6 ,1 -
a]isoquinolinone,
2 -( [1 ,4 ]Dioxany1methoxy)-9 - {3 - [(pyridin-3 -y1methy1)—amino]-prop -1 -yny1} -6,7 -dihydro-pyrimido [6,1 -
a]isoquinolinone,
2-((R) [1 ,4 ]Dioxan-2 -y11nethoxy)-9 -p enty1-6,7-dihydro-pyrimido[6,1-a]isoquinolinone,
9 propy1ethyny1—2-((S) [1 ,4]dioxany1methoxy)-6,7-dihydro-pyrimido [6 1 -a] isoquinolinone,
9 clopropy1—ethy1)((S)[1 ,4]dioxany1methoxy)-6 ,7-dihydro-pyrimido [6 1 -a] isoquinolinone,
2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(oxetan-3 -yloxymethy1)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone,
2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(3 -methy1-oxetan—3 -y1methoxymethy1)—6,7 -dihydro-pyrimido[6,1-
a]isoquinolinone,
9 -(2,2-Dimethy1—buty1amino)((S)[1,4]dioxany1methoxy)—6,7-dihydro-pyrimido[6,1-a]isoquinolin
one,
2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(3 -hydroxy—4-methy1-penty1)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-
4-one,
2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(2-ethy1-hexy1amino)-6,7-dihydro-pyrimido [6 1 -a] isoquinolinone,
2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 thoxy-ethoxy)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone,
2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(2-ethoxy-ethoxy)-6,7 -dihydro-pyrimido [6,1 quinolinone,
9 -Cyclopropy1methoxy((S)[1,4]dioxany1methoxy)—6,7-dihydro-pyrimido[6,1-a]isoquinolinone,
2-((S) [1 xan-2 -y11nethoxy)-9 -(2-fluoro-ethoxy)-6 ,7-dihydro-pyrimido [6 1 -a] isoquinolinone,
2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 - [3 -(2-methoxy—ethoxy)—propyny1]-6,7 -dihydro-pyrimido [6,1 -
a]isoquinolinone,
2-((S)[1,4]Dioxany11nethoxy)-9 -[3 -(2-ethoxy—ethoxy)-propyny1]-6,7-dihydro-pyrimido[6,1-
a]isoquinolinone,
2-((S)[1,4]Dioxany11nethoxy)-9 -[3 oro-ethoxy)-propyny1]-6,7 ro-pyrimido[6,1-
a]isoquinolinone,
9 -(2,2-Dimethy1—propoxymethy1)((S)-1 -[1,4]dioxany1methoxy)-6,7-dihydro-pyrimido[6,1-
a]isoquinolinone,
9 -Cyclohexyloxymethy1((S) [1 ,4]dioxany1methoxy)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone,
9 -Cyclopropylmethoxymethyl—2-((S) [1 ,4]dioxany1methoxy)-6 ,7-dihydro-pyrimido [6 ,1 -a] nolin
one,
2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(tetrahydro-pyrany1methoxy)-6 ,7 ro-pyrimido [6 ,1 -
a]isoquinolinone,
2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(3 -hydroxy—buty1)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolin-4 -one,
9 -(4,4-Dimethy1—pentyloxy)((S)— 1 - [1 ,4]dioxany1methoxy)-6,7-dihydro-pyrimido [6, 1 -a] isoquinolin
one,
[1 ,4]Dioxan-2 -y11nethoxy)-9 -(3 -methoxymethy1—penty1)-6,7-dihydro-pyrimido [6, 1 -a] isoquinolin-
4-one,
9 -(3 -Cyclopropy1—propoxy)((S)[1,4]dioxany1methoxy)—6,7-dihydro-pyrimido[6,1-a]isoquinolin
one,
9 hexy1amino((S)— 1 - [1 ,4]dioxany1methoxy)-6,7-dihydro-pyrimido [6, 1 -a] isoquinolinone,
2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(3 -hydroxy—4,4-dimethy1—penty1)-6,7-dihydro-pyrimido[6,1-
a]isoquinolinone,
9 -Cyclopentylmethoxymethy1((S) [1 ,4]dioxany1methoxy)-6,7-dihydro-pyrimido [6, 1 -a] isoquinolin
one,
[1 xan-2 -y11nethoxy)-9 -(3 -methoxy-buty1)-6,7-dihydro-pyrimido[6,1-a]isoquinolinone,
2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(3 -pheny1amino-propy1)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolin-4 -
one,
2-((S) [1 ,4]Dioxan-2 thoxy)-9 -(4-hydroxy—p enty1)-6,7-dihydro-pyrimido [6, 1 -a] isoquinolinone,
2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(4-hydroxy—buty1)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolinone,
9 -(Cyclohexyl-methyl-amino)((S) [1 ,4]dioxany1methoxy)-6,7-dihydro-pyrimido [6, 1 -a] nolin
one,
9 -(Cyclohexylmethyl-amino)((S)[1,4]dioxany1methoxy)—6,7-dihydro-pyrimido[6,1-a]isoquinolin-4 -
one,
2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 - [(tetrahydro-pyrany1methy1)-amino] -6,7-dihydro-pyrimido[6,1-
a]isoquinolinone,
2-((S) [1 ,4]Dioxan-2 thoxy)-9 -(3 -ethy1-3 -hydroxy—penty1)-6,7-dihydro-pyrimido[6,1-a]isoquinolin
one,
2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(3 -hydroxy—3 -methy1-buty1)-6 ,7 -dihydro-pyrimido [6 ,1 -a]isoquinolin
one,
2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(3 -hydroxy—p enty1)-6,7-dihydro-pyrimido [6, 1 -a] isoquinolinone,
9 -(2,2-Dimethy1—propoxy)((S) [1 ,4]dioxany1methoxy)-6 ,7-dihydro-pyrimido [6 ,1 -a] isoquinolinone,
2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(tetrahydro-pyrany1methoxy)-6 ,7 -dihydro-pyrimido [6 ,1 -
a]isoquinolinone,
2-((S) [1 ,4]Dioxan-2 thoxy)-9 -(4-hydroxy—4-methy1-penty1)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-
4-one,
2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(tetrahydro-pyrany1methoxymethy1)—6,7-dihydro-pyrimido [6, 1 -
a]isoquinolinone,
2 -( [1 ,4 ]Dioxany1methoxy)-9 -methoxy—6,7-dihydro-pyrimido [6, 1 -a] isoquinolinone,
2-((S) [1 ,4]Dioxan-2 -y11nethoxy)-9 -(oxetan-3 -y1methoxy)-6 ,7 ro-pyrimido [6 ,1 -a]isoquinolin-4 -one,
2012/076275
9 -(3 -Cyclopropyl-propoxy)((R)[1 ,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin
one,
2-((S)[1 ,4]Dioxanylmethoxy)-9 -(3 -methoxy-propyl)-6,7 -dihydro-pyrimido [6,1 -a]isoquinolinone,
[1 ,4]Dioxanylmethoxy)-9 -[2-(1-hydroxy-cyclopentyl)-ethyl]-6,7 -dihydro-pyrimido [6,1 -
uinolinone,
2-((R)[1 ,4]Dioxanylmethoxy)-9 -(4-hydroxy-tetrahydro-pyranylethynyl)-6,7 -dihydro-pyrimido [6,1 -
a]isoquinolinone,
In one embodiment, the compound of the invention is selected from:
[1 ,4]Dioxanylmethoxy)-9 -(3 -methoxy-propyl)-6,7 -dihydro-pyrimido [6,1 quinolinone,
2-((R)[1 ,4]Dioxanylmethoxy)-9 -[2-(1 -hydroxy-cyclopentyl)-ethyl] -6,7 -dihydro-pyrimido [6,1 -
a]isoquinolinone,
2-((S)[1 ,4]Dioxanylmethoxy)-9 -(2-propoxy-ethoxy)-6,7 -dihydro-pyrimido [6,1 -a]isoquinolinone,
2-((S)[1 ,4]Dioxanylmethoxy)-9 opropoxy-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolinone,
2-((R)[1,4]Dioxanylmethoxy)(2-propoxy-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolinone,
[1 ,4]Dioxanylmethoxy)-9 -(2-isopropoxy-ethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolinone,
2-((S)[1 ,4]Dioxanylmethoxy)-9 -(4-methoxy-butyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolinone.
In one embodiment, the compound of the invention is 9-cyclopropylethynyl((S)[1,4]dioxan-
2-ylmethoxy)-6,7 -dihydro-pyrimido[6,1 -a]isoquinolinone.
[00141] In another embodiment, the compound of the invention is not opropylethynyl((S)
[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolinone.
] In one embodiment a compound of the invention is not an isotopic variant.
In one aspect a compound of the invention is present as the free base.
] In one aspect a compound of the invention is a pharmaceutically acceptable salt.
[00145] In one aspect a compound of the invention is present as the free base or a pharmaceutically
acceptable salt.
In one aspect a compound of the invention is a solvate.
In one aspect a compound of the invention is a solvate of a ceutically acceptable salt of the
compound.
[00148] In certain aspects, the t invention provides prodrugs and derivatives of a compound of the
invention according to the formula above. Prodrugs are derivatives of a compound of the invention, Which
have metabolically cleavable groups and become by solvolysis or under physiological conditions the
compounds of the invention, which are pharmaceutically active, in vivo. Such examples include, but are not
limited to, choline ester derivatives and the like, N—alkylmorpholine esters and the like.
] Other derivatives of the compounds of this invention have activity in both their acid and acid
derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, or
delayed release in the mammalian sm (see, Bundgard, H. Design of Prodrugs, pp. 7-9, 21-24, Elsevier,
Amsterdam 1985). Prodrugs include acid derivatives well know to tioners of the art, such as, for
e, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction
of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed
anhydrides. Simple aliphatic or ic esters, amides and anhydrides derived from acidic groups pendant
on the compounds of this invention are preferred prodrugs. In some cases it is ble to prepare double
ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particularly useful are
the C1 to C3 alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds
of the invention.
While specified groups for each embodiment have generally been listed above tely, a
compound of the invention includes one in which several or each embodiment in the above Formula, as well
as other formulae presented herein, is selected from one or more of particular members or groups designated
respectively, for each variable. ore, this invention is intended to include all combinations of such
embodiments within its scope.
While specified groups for each embodiment have generally been listed above separately, a
compound of the invention may be one for which one or more variables (for example, R groups) is ed
from one or more embodiments according to any of the Formula(e) listed above. Therefore, the present
invention is intended to include all combinations of variables from any of the disclosed ments within
its scope.
Alternatively, the exclusion of one or more ofthe specified variables from a group or an
embodiment, or combinations thereof is also contemplated by the t ion.
CLAUSES
1. A compound according to Formula la:
WO 92791
wherein
R1 is H, Me, or halo;
L1 is absent or is —O-, -S-, or -NR4a-;
G is
-W-L2-R2, or
-W-L3-R3;
W is C1_4 alkylene, C2_4 lene having one double bond, or C2_4 alkynylene having one triple
bond;
L2 is absent or is —O-;
R2 is
_ H,
- C1_g alkyl, optionally substituted with one to three groups independently selected from
O OH,
O halo,
O CN,
C1_6 alkoxy,
C3_7 cycloalkyl,
4-6 membered heterocycloalkyl comprising one to three heteroatoms ndently
selected from S, and 0,
-6 membered heteroaryl comprising one to three atoms independently selected
from N, S, and O, and
O phenyl,
- C4_7 cycloalkenyl comprising one double bond,
- 5-7 membered heterocycloalkenyl comprising one double bond, and one to three heteroatoms
independently selected from N, O, and S,
- C3_7 cycloalkyl optionally substituted With one or more independently selected R5 groups,
- 4-10 membered heterocycloalkyl comprising one to two heteroatoms independently selected
from S, and O, optionally substituted with one to three independently selected R5 groups,
- 5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N,
S, and O optionally substituted with one to three independently ed R6 groups, or
- C640 aryl optionally substituted with one or more independently ed R6 groups;
L3 is -NR4b-;
R3 is
- C1_4 alkyl substituted With
0 C640 aryl optionally substituted with one or more independently selected R7 groups, or
0 5-10 membered heteroaryl comprising one to three heteroatoms independently selected
from N, S, and O, optionally substituted with one or more R independently selected R7
groups,
-10 ed heteroaryl comprising one to three heteroatoms independently selected from N,
S, and O, optionally substituted With one or more independently selected R7 group, or
- €6.10 aryl ally substituted with one or more independently selected R7 groups;
Each R4&1 and R4b is independently selected from H, C14 alkyl, and C3_7 lkyl;
R5 is oxo or R6;
R6 is
- OH,
- halo,
- -NOZ,
- C1_6 alkyl optionally substituted With one to three groups independently selected from halo, and
- C1_6 alkoxy optionally substituted With one to three groups ndently selected from halo, and
OH,
- C3_7 cycloalkyl,
- -C(=O)OR8,
- -C(=O)NR9R1°,
- -NHC(=O)-C1_4 alkyl,
- -CN,
- phenyl,
- -O-phenyl,
- 4-7 membered heterocycloalkyl comprising one to three heteroatoms ndently selected
from N, O, and S, or
- 5-6 membered heteroaryl comprising one to three heteroatoms independently selected from N, O,
and S, optionally substituted with one or more indepentently selected C14 alkyl, C1_4 alkoxy, CN,
halo), and -C(=O)OR“;
R7 is C1_4 alkyl, or halo; and
each of R8, R9, R10 and R11 is independently selected from H and C1_4 alkyl,
or a pharmaceutically acceptable salt, or a solvate, or a solvate of the pharmaceutically acceptable
salt.
2. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the nd
is according to Formula lb:
lb
wherein R1, L1 and G are as usly bed.
3. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the nd
is according to Formula Ic:
wherein R1, L1 and G are as previously described.
A compound or pharmaceutically acceptable salt thereof, according to any one of s 1-3, wherein
R1 is Me, F, or Cl.
A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-3, wherein
R1 is H.
A compound or pharmaceutically acceptable salt thereof, according to clause 1 or 2, wherein the
compound is according to Formula Ila, Ilb or Hc:
ofi o ofi
L1—R2 L1—R2 L1—R2
Ila Ilb ||c
wherein L1, and R2 are as described in claim 1.
A compound or pharmaceutically acceptable salt f, according to clause 1 or 2, wherein the
compound is according to Formula Illa, Illb, or IIIc:
ofi ofi ofi
aO 2O r
O O o
I N’ N/
I I I
o N CAN 0 N
/W\ /R2 /W\ /R2
L1 L2 L1 L2 L1/W\L/ R22
Illa |||b IIIc
n L, W, L2, and R2 are as decribed previously.
A compound or pharmaceutically acceptable salt thereof, according to clause 1 or 2, n the
compound is according to Formula IVa, lVb, or IVc:
ofi o ofi
W\ R3 W\ R3 W\ R3
LT Lg L7 Lg L1 L3
IVa IVb IVC
wherein L, W, L3, and R3 are as described in claim 1.
A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-8, wherein
L1 is absent.
. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-8, wherein
L1 is—O-.
11. A nd or ceutically acceptable salt thereof, according to any one of clauses 1-8, wherein
L1 is -NR4a-, and R4&1 is H, Me, Et, or cyclopropyl.
12. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-8, wherein
L1 is -NR4a-, and R4a is H.
13. A compound or pharmaceutically able salt thereof, according to any one of clauses 1-5, or 7-11,
wherein W is C1_4 alkylene.
14. A compound or pharmaceutically acceptable salt thereof, according to clause 13, n W is —CH2-,
—CH2-CH2-, —CH2-CH2-CH(CH3)-, —CH2-CH(-CH2-CH3)-, —CH2-C(CH3)2-, or —CH2-CH2-CH2-.
. A compound or pharmaceutically acceptable salt thereof, ing to clause 14, wherein W is —CH2-
CH2-.
16. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-5, or 7-11,
wherein W is C2_4 alkenylene having one double bond.
17. A compound or pharmaceutically able salt thereof, according to clause 16, wherein W is —
CH=CH-, —CH2-CH=CH-, or -CH=CH-CH2.
18. A compound or pharmaceutically acceptable salt thereof, according to clause 17, wherein W is -
CH=CH-.
19. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-5, or 7-11,
wherein W is C2_4 alkynylene haVing one triple bond.
. A compound or pharmaceutically acceptable salt thereof, according to clause 19, wherein W is —CEC-,
—CH2-CEC-, or H2-.
21. A compound or pharmaceutically able salt thereof, according to clause 20, wherein W is -CEC-.
22. A compound or pharmaceutically able salt thereof, according to any one of clauses 1-5, 7, or 9-
21, wherein L2 is —O-.
23. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-5, 7, or 9-
21, wherein L2 is absent.
24. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-5, 7, or 9-
21, wherein L1 and L2 are absent, and W is -CH2-, H2-, or H2-CH2-.
. A compound or pharmaceutically able salt thereof, according to clause 1-5, 7, or 9-21, wherein
L1 and L2 are absent, and W is -CH=CH-, -CH2-CH=CH-, or -CH2-.
26. A compound or pharmaceutically acceptable salt thereof, according to clause 1-5, 7, or 9-21, wherein
L1 and L2 are absent, and W is -CEC-, -CH2-CEC-, or -CEC-CH2-.
27. A nd or pharmaceutically acceptable salt thereof, according to any one of clauses 1-7, or 9-25,
wherein R2 is H.
28. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-7, or 9-25,
n R2 is CH; alkyl.
29. A compound or ceutically acceptable salt thereof, according to clause 28, wherein R2 is Me, Et,
n-Pr, i-Pr, i-Bu, or l—Bu.
. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-7, or 9-25,
n R2 is CH; alkyl substituted with one group selected from OH, halo, CN, C1_6 alkoxy, C3_7
cycloalkyl, 4-6 membered heterocycloalkyl (comprising one to three heteroatoms independently
selected from S, and O), 5-6 membered heteroaryl (comprising one to three heteroatoms independently
selected from N, S, and O), and .
31. A compound or pharmaceutically able salt thereof, ing to any one of clauses 1-7, or 9-25,
wherein R2 is Me, Et, n-Pr, i-Pr, i-Bu, or t—Bu, each of which is substituted with one group selected
from OH, halo, CN, C1_6 alkoxy, C3_7 cycloalkyl, 4-6 ed heterocycloalkyl (comprising one to
three heteroatoms independently selected from S, and O), 5-6 membered heteroaryl (comprising one to
three heteroatoms independently selected from N, S, and O), and phenyl.
32. A compound or pharmaceutically acceptable salt f, according to any one of clause 30, wherein
R2 is C1_g alkyl substituted with one group selected from OH, F, Cl, CN, -OMe, -OEt, -Oz'-Pr,
cyclopropyl, utyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrralolyl, imidazolyl,
triazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and .
33. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-7, or 9-25,
n R2 is C4_7 cycloalkenyl comprising one double bond.
34. A compound or pharmaceutically able salt thereof, according to clause 33, wherein R2 is
cyclohexenyl.
35. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-7, or 9-25,
wherein R2 is 5-7 membered heterocycloalkenyl comprising one double bond, and one to three
heteroatoms independently selected from N, O, and S.
36. A compound or pharmaceutically acceptable salt thereof, according to clause 35, wherein R2 is
dihydropyranyl.
37. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-7, or 9-25,
n R2 is C3_7 cycloalkyl.
38. A compound or pharmaceutically acceptable salt f, according to any one of clauses 1-7, or 9-25,
wherein R2 is C3_7 cycloalkyl substituted with one R5 group.
39. A compound or pharmaceutically acceptable salt thereof, according to clause 38, wherein R5 is oxo, or
R6 wherein R6 is selected from OH, and CM alkyl.
40. A compound or pharmaceutically acceptable salt thereof, according to clauses 37, 38 or 39, wherein R2
is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
41. A nd or pharmaceutically acceptable salt thereof, according to any one of clauses 1-7, or 9-25,
wherein R2 is 4-10 membered cycloalkyl comprising one to two heteroatoms independently
selected from S, and O.
42. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-7, or 9-25,
wherein R2 is 4-10 membered heterocycloalkyl comprising one to two heteroatoms independently
selected from S, and O, substituted with one R5 group.
43. A compound or pharmaceutically acceptable salt thereof, according to clause 42, wherein R5 is selected
from oxo, or R6 wherein R6 is selected from OH, and C1_6 alkyl.
44. A compound or pharmaceutically acceptable salt thereof, according to clause 41, 42 or 43, wherein R2
is yl, tetrahydrofuranyl, ydropyranyl, or yl.
45. A compound or pharmaceutically acceptable salt thereof, according to any one of s 1-7, or 9-25,
wherein R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected
from N, S, and O.
46. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-7, or 9-25,
wherein R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected
from N, S, and O, substituted with one or two independently selected R6 groups.
47. A compound or pharmaceutically acceptable salt thereof, according to clause 46, wherein each R6 is
independently selected from OH, halo, C1_6 alkyl, C1_6 alkyl substituted with one or more halo, C1_6
alkoxy, -CN, C3_7 lkyl 4-7 membered cycloalkyl comprising one to three heteroatoms
independently selected from N, O, and S, and phenyl.
48. A compound or pharmaceutically acceptable salt thereof, according to clause 45, 46 or 47, wherein R2
is l, thienyl, oxazolyl, thiazolyl, zolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl,
pyrazinyl, pyrimidinyl, indanyl, or indazolyl.
49. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-7, or 9-25,
n R2 is C640 aryl.
50. A compound or pharmaceutically acceptable salt thereof, according to any one of s 1-7, or 9-25,
wherein R2 is €6.10 aryl, tuted with one or two independently selected R6 groups.
51. A compound or pharmaceutically acceptable salt f, according to clause 50, wherein R6 is selected
from halo, CN, CM alkyl, CM alkoxy, -NHC(=O)-C1_4 alkyl, and -C(=O)NR9R1°, wherein each R9 and
R10 is ndently selected from from H and C1_4 alkyl.
52. A compound or pharmaceutically acceptable salt thereof, ing to clause 49, 50 or 51, wherein R2
is phenyl.
53. A compound or pharmaceutically acceptable salt f, according to any one of clauses 1-5, or 8-21,
wherein L3 is -NR4b-, and R4b is H, Me, Et, or cyclopropyl.
54. A compound or pharmaceutically able salt thereof, according to any one of clauses 1-5, or 8-21,
wherein R3 is C1_4 alkyl substituted with phenyl, or pyridyl.
55. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-5, or 8-21,
wherein R3 is C1_4 alkyl substituted with phenyl, or pyridyl, each of which is substituted with Me, Et, F,
or Cl
56. A nd or pharmaceutically acceptable salt f, according to any one of s 1-5, or 8-21,
wherein R3 is 5-10 membered heteroaryl sing one to three heteroatoms independently selected
from N, S, and O.
57. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-5, or 8-21,
wherein R3 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected
from N, S, and O, substituted with one or more independently selected R7 groups.
58. A compound or pharmaceutically acceptable salt f, according to clause 57 wherein R7 is selected
from Me, Et, F, and Cl.
59. A compound or ceutically acceptable salt thereof, according to clause 56, 57, or 58 wherein R3
is pyridyl.
60. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-5, or 8-21,
n R3 is C640 aryl.
61. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-5, or 8-21,
wherein R3 is C640 aryl, substituted with one or more independently selected R7 groups.
62. A compound or pharmaceutically acceptable salt thereof, ing to clause 61, wherein R7 is selected
from Me, Et, F, and Cl.
63. A compound or pharmaceutically acceptable salt f, according to clause 60, 61, or 62, wherein R3
is phenyl.
64. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound
is according to Formula Va:
wherein R2 is as bed previously.
65. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound
is according to Formula Vb:
wherein R2 is as described previously.
66. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound
is according to Formula Vc:
o R2
n R2 is as described previously.
67. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound
is ing to Formula Vd:
wherein R2 is as described previously.
68. A compound or pharmaceutically acceptable salt thereof, ing to clause 1, wherein the compound
is ing to Formula Vla:
wherein R2 is as described previously.
69. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound
is according to Formula Vlb:
wherein R2 is as described preViously.
70. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound
is according to Formula Vlc:
wherein R2 is as bed preViously.
71. A compound or pharmaceutically acceptable salt f, according to clause 1, wherein the nd
is according to Formula Vld:
wherein R2 is as described previously.
72. A nd or pharmaceutically acceptable salt thereof, according to clause 1, wherein the nd
is according to Formula Vlla:
Vlla
wherein R2 is as described preViously.
73. A nd or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound
is according to Formula Vllb:
Vllb
wherein R2 is as described preViously.
74. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound
is according to Formula VIIc:
o N
OARZ
VIIC
n R2 is as described previously.
75. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound
is according to Formula Vlld:
Vlld
wherein R2 is as described preViously.
76. A compound or pharmaceutically acceptable salt thereof, according to clause 64, 65, 68, 69, 72, or 73,
n R2 is C3_7 cycloalkyl.
77. A compound or pharmaceutically acceptable salt thereof, according to clause 64, 65, 68, 69, 72, or 73,
n R2 is C3_7 cycloalkyl substituted with one R5 group.
78. A compound or pharmaceutically acceptable salt thereof, according to clause 77, wherein R5 is oxo, or
R6 wherein R6 is OH, or C1_6 alkyl.
79. A compound or pharmaceutically acceptable salt thereof, according to clause 76, 77 or 78, wherein R2
is cyclopropyl, utyl, cyclopentyl or cyclohexyl.
80. A compound or pharmaceutically able salt thereof, according to clause 66, 67, 70, 71, 74, or 75,
wherein R2 is 5-10 ed heteroaryl comprising one to three atoms independently selected
from N, S, and O.
81. A compound or pharmaceutically acceptable salt thereof, according to clause 66, 67, 70, 71, 74, or 75,
wherein R2 is 5-10 membered heteroaryl comprising one to three heteroatoms independently selected
from N, S, and O, substituted with one or two independently selected R6 groups.
82. A compound or pharmaceutically acceptable salt thereof, according to clause 81, wherein R6 is selected
from OH, halo, CM alkyl, C1_6 alkyl substituted with one or more halo, CM alkoxy, -CN, C3_7
WO 92791
cycloalkyl 4-7 membered sing one to three heteroatoms
, heterocycloalkyl independently
selected from N, O, and S, and phenyl.
83. A compound or pharmaceutically acceptable salt thereof, ing to clause 80, 81 or 82, wherein R2
is furanyl, thienyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridinyl,
pyrazinyl, pyrimidinyl, indanyl, or indazolyl.
84. A compound or pharmaceutically acceptable salt f, according to clause 66, 67, 70, 71, 74, or 75,
wherein R2 is C640 aryl.
85. A compound or pharmaceutically acceptable salt thereof, according to clause 66, 67, 70, 71, 74, or 75,
wherein R2 is C640 aryl substituted with one or two independently selected R6 groups.
86. A compound or pharmaceutically acceptable salt thereof, according to clause 85, n R6 is selected
from halo, CN, C1_6 alkyl, C1_6 alkoxy, -NHC(=O)-C1_4 alkyl, and -C(=O)NR9R10, and each R9 and R10
is independently selected from from H and C1_4 alkyl.
87. A compound or pharmaceutically acceptable salt thereof, according to clause 84, 85 or 86, wherein R2
is phenyl.
88. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound
is 9-cyclopropylethynyl((S)-1 -[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1 -a]isoquinolin
one.
89. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound
is not 9-cyclopropylethynyl((S)-1 -[1,4]dioxanylmethoxy)-6,7 -dihydro-pyrimido [6,1 -
a]isoquinolinone.
PHARMACEUTICAL COMPOSITIONS
When employed as a pharmaceutical, a compound of the invention is typically stered in the
form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the
ceutical art and comprise at least one active compound. Generally, a compound of the invention is
administered in a pharmaceutically effective amount. The amount of a compound actually administered will
typically be determined by a physician, in the light of the relevant circumstances, ing the condition to
be treated, the chosen route of administration, the actual compound -administered, the age, weight, and
response of the individual patient, the severity of the t’s symptoms, and the like.
The ceutical compositions of the invention can be administered by a y of routes
including oral, , transdermal, subcutaneous, intra-articular, enous, intramuscular, intranasal and
tion. Depending on the intended route of delivery, a compound of this invention is preferably
formulated as either able or oral compositions or as salves, as lotions or as patches all for transdermal
administration.
The itions for oral administration can take the form of bulk liquid solutions or suspensions,
or bulk powders. More commonly, however, the itions are presented in unit dosage forms to facilitate
accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages
for human subjects and other mammals, each unit containing a predetermined quantity of active material
calculated to produce the desired therapeutic , in association with a suitable pharmaceutical excipient,
vehicle or carrier. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid
compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, a
compound of the invention is usually a minor component (from about 0.1 to about 50% by weight or
preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and
processing aids helpful for forming the desired dosing form.
Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous
vehicle with buffers, suspending and dispensing , colorants, flavors and the like. Solid forms may
include, for example, any of the ing ingredients, or compounds of a similar nature: a binder such as
microcrystalline cellulose, gum anth or gelatin; an excipient such as starch or lactose, a disintegrating
agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as
colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as
peppermint, methyl salicylate, or orange flavoring.
[00157] Injectable compositions are lly based upon injectable e saline or ate-buffered
saline or other inj ectable carriers known in the art. As before, the active compound in such compositions is
lly a minor component, often being from about 0.05 to 10% by weight with the remainder being the
inj ectable carrier and the like.
ermal compositions are typically formulated as a topical ointment or cream containing the
active ient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from
about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more ably
from about 0.5 to about 15% by weight. When formulated as a ointment, the active ingredients will typically
be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients
may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations
are well-known in the art and generally include onal ingredients to enhance the dermal penetration of
stability of the active ingredients or the formulation. All such known transdermal formulations and
ingredients are included within the scope of this ion.
] A compound of the invention can also be administered by a transdermal device. Accordingly,
transdermal administration can be accomplished using a patch either of the reservoir or porous membrane
type, or of a solid matrix variety.
] The above-described components for orally administrable, inj ectable or topically administrable
compositions are merely representative. Other materials as well as sing techniques and the like are set
forth in Part 8 of Remington’s Pharmaceutical Sciences, 17th edition, 1985, Mack hing Company,
, Pennsylvania, which is incorporated herein by reference.
A compound of the invention can also be administered in sustained release forms or from
sustained release drug delivery systems. A description of entative sustained release materials can be
found in Remington’s Pharmaceutical es.
The following formulation examples illustrate representative ceutical compositions that
may be prepared in accordance with this invention. The present ion, however, is not limited to the
following pharmaceutical compositions.
Formulation 1 - Tablets
A compound of the invention may be admixed as a dry powder with a dry gelatin binder in an
approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The
mixture may be formed into 240-270 mg tablets (80-90 mg of active amide compound per tablet) in a tablet
press.
Formulation 2 - Capsules
A compound of the invention may be admixed as a dry powder with a starch diluent in an
approximate 1:1 weight ratio. The mixture may be filled into 250 mg capsules (125 mg of active amide
compound per capsule).
Formulation 3 - Liquid
] A compound of the invention (125 mg), may be d with sucrose (1.75 g) and xanthan gum
(4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed
with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50
mg) in water. Sodium benzoate (10 mg), flavor, and color may be diluted with water and added with stirring.
Sufficient water may then be added with stirring. Sufficient water may be then added to produce a total
volume of 5 mL.
Formulation 4 - Tablets
A compound of the invention may be admixed as a dry powder with a dry n binder in an
approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The
mixture is formed into 0 mg s (150-300 mg of active amide compound) in a tablet press.
Formulation 5 - Injection
A compound of the invention may be dissolved or suspended in a buffered sterile saline injectable
aqueous medium to a concentration of approximately 5 mg/mL.
Formulation 6 - Topical
Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75°C and then a
mixture of a compound of the invention (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl
sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting
e may be stirred until it congeals.
METHODS OF ENT
A compound of the invention may be used as a therapeutic agent for the treatment of conditions in
mammals that are causally related or attributable to aberrant ty of GPR84 and/or aberrant GPR84
sion and/or aberrant GPR84 distribution.
Accordingly, a compound and pharmaceutical compositions of the invention find use as
therapeutics for the prophylaxis and/or treatment of inflammatory conditions (e.g. atory bowel
diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease
(COPD) and lung interstitial es (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory
conditions, ious diseases, autoimmune diseases, endocrine and/or lic diseases, and/or diseases
involving impairment of immune cell fimctions, in mammals including humans.
Accordingly, in one aspect, the t invention provides the compound of the invention, or a
pharmaceutical ition comprising the compound of the invention for use as a medicament.
] In another aspect, the present invention provides the compound of the invention, or a
pharmaceutical composition comprising the compound of the invention for use in the manufacture of a
medicament.
In yet another aspect, the present invention provides a method of treating a mammal having, or at
risk of having a disease disclosed herein. In a particular aspect, the present invention provides a method of
treating a mammal having, or at risk of having atory ions (e.g. inflammatory bowel es
(IBD), rheumatoid arthritis, vasculitis, lung diseases (e. g. chronic obstructive pulmonary disease (COPD) and
lung interstitial diseases (e. g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious
diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of
immune cell fimctions, in mammals including humans.
[00174] In one aspect, the present invention provides the compound of the invention, or a pharmaceutical
composition comprising the compound of the invention for use as a ne for the prophylaxis and/or
treatment of inflammatory conditions. In a specific embodiment, the inflammatory condition is selected from
atory bowel disease (IBD), rheumatoid arthritis, itis, chronic obstructive pulmonary disease
, and idiopathic pulmonary fibrosis (IPF).
In another aspect, the present invention provides the compound ofthe invention, or a
pharmaceutical composition comprising the compound of the invention for use in the manufacture of a
medicament for the prophylaxis and/or treatment of inflammatory conditions. In a specific embodiment, the
inflammatory condition is selected from inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis,
chronic ctive ary disease (COPD), and idiopathic pulmonary fibrosis (IPF).
In additional method of treatment aspects, this invention provides methods of treatment and/or
prophylaxis of a mammal susceptible to or afflicted with inflammatory conditions, which method comprises
administering an ive amount of a compound of the ion, or one or more of the pharmaceutical
compositions herein described. In a specific embodiment, the inflammatory condition is selected from
inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis, chronic obstructive pulmonary disease
(COPD), and idiopathic pulmonary fibrosis (IPF).
In another aspect, the present ion es a method of treating a mammal having, or at risk
of having a disease selected from inflammatory conditions (for e inflammatory bowel diseases (IBD),
rheumatoid arthritis, vasculitis, lung diseases (e. g. chronic obstructive pulmonary disease (COPD) and lung
interstitial diseases (e. g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious
diseases, autoimmune es, endocrine and/or metabolic es, and/or diseases involving impairment of
immune cell fiJnctions.
In one aspect, the present invention provides the compound of the invention, or a pharmaceutical
composition sing the nd of the invention for use as a medicine for the prophylaxis and/or
treatment of nflammatory conditions, Guillain-Barré syndrome (GB S), multiple sclerosis, axonal
degeneration, autoimmune encephalomyelitis.
In r aspect, the present invention provides the compound ofthe invention, or a
pharmaceutical composition comprising the compound of the invention for use in the cture of a
medicament for the prophylaxis and/or treatment of neuroinflammatory conditions, Guillain-Barré syndrome
(GB S), multiple sclerosis, axonal degeneration, autoimmune encephalomyelitis.
In additional method of ent aspects, this invention provides methods of ent and/or
prophylaxis of a mammal susceptible to or afflicted with neuroinflammatory conditions, Guillain-Barré
syndrome (GBS), multiple sclerosis, axonal degeneration, autoimmune encephalomyelitis, which method
comprises administering an effective amount of a compound of the invention, or one or more of the
pharmaceutical compositions herein described.
] In one aspect, the present invention provides the compound of the ion, or a pharmaceutical
composition comprising the compound of the invention for use as a medicine for the prophylaxis and/or
ent of ious e. In a specific embodiment, the infectious diseases is selected from sepsis,
septicemia, endotoxemia, ic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis,
tuberculosis, and other infections involving, for example, Yersinia, ella, Chlamydia, Shigella,
enterobacteria species.
In another aspect, the present invention provides the compound ofthe invention, or a
pharmaceutical composition comprising the compound of the invention for use in the manufacture of a
ment for the prophylaxis and/or treatment of infectious disease. In a specific embodiment, the
infectious diseases is selected from , septicemia, endotoxemia, systemic inflammatory se
syndrome (SIRS), gastritis, enteritis, colitis, tuberculosis, and other infections involving, for example,
Yersinia, Salmonella, Chlamydia, Shigella, enterobacteria species.
In additional method of ent aspects, this invention provides methods of treatment and/or
prophylaxis of a mammal susceptible to or afflicted with infectious disease, which method ses
administering an effective amount of a nd of the invention, or one or more of the pharmaceutical
compositions herein described. In a specific embodiment, the infectious diseases is selected from sepsis,
septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis,
tuberculosis, and other ions involving, for example, Yersinia, Salmonella, Chlamydia, Shigella,
enterobacteria species.
In one aspect, the present invention provides the compound of the invention, or a pharmaceutical
composition comprising the compound of the invention for use as a medicine for the prophylaxis and/or
treatment of autoimmune diseases, and/or diseases involving impairment of immune cell functions. In a
specific embodiment, the autoimmune diseases and/or diseases involving impairment of immune cell
functions is ed from COPD, asthma, psoriasis, systemic lupus erythematosis, type I es mellitus,
vasculitis and inflammatory bowel disease.
In another aspect, the present invention provides the nd ofthe invention, or a
pharmaceutical composition comprising the compound of the invention for use in the manufacture of a
medicament for the prophylaxis and/or treatment of autoimmune es and/or diseases involving
impairment of immune cell ons. In a specific ment, the autoimmune diseases, and/or diseases
ing impairment of immune cell fiJnctions is selected from COPD, asthma, psoriasis, systemic lupus
matosis, type I diabetes mellitus, vasculitis and inflammatory bowel disease.
] In additional method of treatment aspects, this invention provides methods of treatment and/or
prophylaxis of a mammal susceptible to or afflicted with autoimmune diseases and/or diseases involving
impairment of immune cell functions, which method comprises administering an effective amount of a
compound of the invention, or one or more of the pharmaceutical compositions herein described. In a
specific embodiment, the autoimmune diseases and/or diseases involving ment of immune cell
ons is selected from COPD, asthma, psoriasis, systemic lupus erythematosis, type I diabetes mellitus,
itis and inflammatory bowel disease.
2012/076275
In one aspect, the present invention provides the compound of the invention, or a pharmaceutical
ition comprising the compound of the invention for use as a medicine for the prophylaxis and/or
treatment of endocrine and/or metabolic diseases. In a specific embodiment, the endocrine and/or metabolic
diseases is selected from hypothyroidism, ital l hyperplasia, diseases of the parathyroid gland,
diabetes mellitus, es of the adrenal glands (including Cushing’s syndrome and Addison’s disease),
ovarian dysfunction (including stic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes,
hyperlipidemia, gout, and rickets.
In another aspect, the present invention provides the compound of the invention, or a
pharmaceutical composition comprising the compound of the invention for use in the manufacture of a
medicament for the prophylaxis and/or treatment of endocrine and/or metabolic diseases. In a specific
ment, the endocrine and/or metabolic diseases is selected from hypothyroidism, congenital adrenal
hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the l glands (including
g’s syndrome and Addison’s disease), ovarian ction (including polycystic ovary syndrome),
cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.
[00189] In additional method of treatment aspects, this invention provides methods of treatment and/or
prophylaxis of a mammal susceptible to or afflicted with endocrine and/or metabolic diseases, Which method
comprises stering an effective amount of a compound of the invention, or one or more of the
pharmaceutical compositions herein described. In a specific embodiment, the endocrine and/or metabolic
diseases is ed from hypothyroidism, congenital l hyperplasia, diseases of the parathyroid gland,
diabetes mellitus, diseases of the adrenal glands (including Cushing’s syndrome and Addison’s disease),
ovarian dysfunction (including polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes,
hyperlipidemia, gout, and rickets.
As a further aspect of the invention there is ed a nd of the invention for use as a
medicament especially in the treatment or prevention of the aforementioned conditions and diseases. Also
provided herein is the use of the compound in the manufacture of a medicament for the treatment or
prevention of one of the aforementioned conditions and diseases.
A particular regimen of the present method comprises the administration to a subject in ing
from an inflammatory condition, of an effective amount of a nd of the ion for a period of time
sufficient to reduce the level of inflammation in the subject, and preferably terminate, the processes
responsible for said inflammation. A special ment of the method comprises administering of an
effective amount of a compound of the invention to a subject suffering from or susceptible to the
development of inflammatory condition for a period of time sufficient to reduce or prevent, respectively,
inflammation of said patient, and preferably ate, the ses responsible for said inflammation.
Injection dose levels range from about 0.1 mg/kg/h to at least 10 mg/kg/h, all for from about 1 to
about 120 h and especially 24 to 96 h. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or
2012/076275
more may also be administered to achieve te steady state levels. The maximum total dose is not
expected to exceed about 2 g/day for a 40 to 80 kg human patient.
Transdermal doses are generally selected to provide similar or lower blood levels than are
achieved using injection doses.
When used to prevent the onset of a condition, a compound of the invention will be administered
to a patient at risk for ping the condition, typically on the advice and under the supervision of a
physician, at the dosage levels described above. Patients at risk for ping a particular condition
generally include those that have a family history of the condition, or those who have been identified by
genetic testing or screening to be particularly susceptible to developing the condition.
[00195] A compound of the ion can be administered as the sole active agent or it can be
administered in combination with other therapeutic agents, including other compounds that demonstrate the
same or a similar therapeutic activity, and that are determined to be safe and efficacious for such combined
administration. In a specific embodiment, co-administration of two (or more) agents allows for significantly
lower doses of each to be used, thereby reducing the side s seen.
[00196] In one embodiment, a compound of the invention is co-administered with another therapeutic
agent for the treatment and/or prevention of an atory condition; particular agents include, but are not
limited to, immunoregulatory agents e.g. oprine, corticosteroids (e. g. solone or dexamethasone),
cyclophosphamide, cyclosporin A, tacrolimus, Mycophenolate Mofetil, muromonab-CD3 (OKT3, e.g.
Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and cam.
[00197] In one embodiment, a compound of the invention is co-administered with another therapeutic
agent for the treatment and/or prevention of arthritis (e. g. rheumatoid arthritis); ular agents include but
are not limited to analgesics, non-steroidal anti-inflammatory drugs (NSAIDS), steroids, synthetic DMARDS
(for e but without limitation methotrexate, leflunomide, sulfasalazine, auranofin, sodium
aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, and cyclosporin), and
biological DMARDS (for example but without limitation Infliximab, Etanercept, Adalimumab, Rituximab,
mab, Certolizumab pegol, Tocilizumab, Interleukin 1 blockers and Abatacept).
In one embodiment, a nd of the invention is co-administered with another therapeutic
agent for the treatment and/or tion of autoimmune diseases; particular agents include but are not
limited to: glucocorticoids, cytostatic agents (e. g. purine analogs), alkylating agents, (e.g nitrogen mustards
(cyclophosphamide), nitrosoureas, platinum compounds, and others), tabolites (e.g. methotrexate,
azathioprine and topurine), cytotoxic antibiotics (e. g. dactinomycin anthracyclines, cin C,
bleomycin, and mithramycin), antibodies(e.g., anti-CD20, anti-CD25 or D3 (OTK3) monoclonal
antibodies, Atgam® and Thymoglobuline®), cyclosporin, tacrolimus, rapamycin (sirolimus), interferons (e.g.
IFN—B), TNF binding proteins (e.g. infliximab (RemicadeTM), cept (EnbrelTM), or adalimumab
(HumiraTM)), mycophenolate, Fingolimod, and Myriocin.
In one embodiment, a compound of the invention is inistered with another therapeutic
agent for the treatment and/or prevention of infectious diseases; particular agents include but are not limited
to antibiotics. In a particular embodiment, a compound of the invention is co-administered With another
therapeutic agent for the treatment and/or prevention of infections of any organ of the human body; particular
agents include but are not limited to: aminoglycosides, ansamycins, carbacephem, carbapenems,
cephalosporins, glycopeptides, amides, macrolides, monobactams, nitrofurans, penicillins,
ptides, quinolones, sulfonamides, tetracyclins, anti-mycobacterial agents, as well as chloramphenicol,
fosfomycin, linezolid, metronidazole, cin, rifamycin, thiamphenicol and tinidazole.
In one embodiment, a nd of the invention is inistered with r therapeutic
agent for the treatment and/or prevention of vasculitis, particular agents include but are not limited to steroids
(for example prednisone, prednisolone), cyclophosphamide and eventually antibiotics in case of cutaneous
infections (for example cephalexin)
In one ment, a compound of the invention is co-administered With r therapeutic
agent for the treatment and/or tion of IPF, ular agents include but are not limited to pirfenidone
and bosentan.
In one embodiment, a compound of the invention is co-administered With another therapeutic
agent for the treatment and/or prevention of asthma and/or rhinitis and/or COPD, particular agents include
but are not limited to: betaZ-adrenoceptor agonists (e. g. salbutamol, levalbuterol, terbutaline and bitolterol),
epinephrine (inhaled or tablets), anticholinergics (e.g. opium bromide), glucocorticoids (oral or inhaled)
Long-acting BZ-agonists (e.g. salmeterol, formoterol, bambuterol, and ned-release oral albuterol),
combinations of inhaled steroids and long-acting bronchodilators (e. g. fluticasone/salmeterol,
budesonide/formoterol), leukotriene antagonists and synthesis inhibitors (e.g. montelukast, zafirlukast and
zileuton), tors of mediator release (e.g. lycate and ketotifen), phosphodiesterase-4 inhibitors
(e.g. Roflumilast), biological regulators of IgE response (e.g. umab), antihistamines (e.g. zine,
cinnarizine, fexofenadine), and vasoconstrictors (e.g. oxymethazoline, thazoline, nafazoline and
tramazoline).
Additionally, a compound of the invention may be administered in combination With emergency
therapies for asthma and/or COPD, such therapies include oxygen or heliox administration, nebulized
salbutamol or terbutaline (optionally combined With an anticholinergic (e.g. ipratropium), systemic steroids
(oral or intravenous, e.g. prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone),
intravenous salbutamol, non-specific beta-agonists, injected or inhaled (e. g. hrine, isoetharine,
isoproterenol, metaproterenol), anticholinergics (IV or nebulized, e.g. glycopyrrolate, atropine, ipratropium),
xanthines (theophylline, aminophylline, bamiphylline), tion anesthetics that have a
bronchodilatory effect (e.g. isoflurane, halothane, enflurane), ketamine, and intravenous magnesium sulfate.
] In one embodiment, a compound of the invention is co-administered with another therapeutic
agent for the treatment and/or prevention of inflammatory bowel disease (IBD); particular agents include but
are not limited to: glucocorticoids (e.g. prednisone, budesonide) synthetic disease modifying,
modulatory agents (e.g. rexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6-
mercaptopurine and ciclosporin) and biological disease ing, immunomodulatory agents (infliximab,
adalimumab, rituximab, and abatacept).
By co-administration is included any means of delivering two or more therapeutic- agents to the
patient as part of the same treatment regime, as will be nt to the skilled person. Whilst the two or more
agents may be administered simultaneously in a single formulation this is not essential. The agents may be
administered in different formulations and at different times.
GENERAL SYNTHETIC PROCEDURES
General
A compound of the invention can be prepared from readily available starting materials using the
following general methods and procedures. It will be appreciated that where typical or preferred s
conditions (i.e., on temperatures, times, mole ratios of nts, ts, pressures, etc.) are given,
other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary
with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art
by routine optimization procedures.
[00207] Additionally, as will be nt to those skilled in the art, conventional protecting groups may be
necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable
protecting group for a particular functional group as well as suitable conditions for protection and
ection are well known in the art. For example, numerous protecting groups, and their introduction and
removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Wiley-
Blackwell; 4th Revised edition edition (2006), and references cited therein.
] The following methods are presented with details as to the preparation of representative 6,7-
dihydro-pyrimido[6,1-a]isoquinolinone that have been listed hereinabove. A compound of the invention
may be prepared from known or commercially ble starting materials and reagents by one skilled in the
art of organic synthesis.
[00209] All reagents were of commercial grade and were used as received t r purification,
unless otherwise stated. Commercially available anhydrous solvents were used for ons conducted under
inert atmosphere. Reagent grade ts were used in all other cases, unless otherwise specified. Column
chromatography was performed on silica standard (30-70 um). Thin layer chromatography was carried out
using pre-coated silica gel 60 F-254 plates (thickness 0.25 mm). 1H NMR spectra were recorded on a Bruker
e 400 NMR spectrometer (400 MHz) or a Bruker Advance 300 NMR spectrometer (300 MHz).
Chemical shifts (5) for 1H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane
(5 0.00) or the appropriate al solvent peak as internal reference. Multiplicities are given as singlet (s),
doublet (d), doublet of doublet (dd), triplet (t), t (q), multiplet (m) and broad (br). Electrospray MS
a were obtained either on a Waters platform LC/MS spectrometer or on an Agilent 1100 Series
. Analytic LCMS: Columns used, Waters Acquity UPLC BEH C18 1.7um, 2.1mm ID x 50mm L or
Waters Acquity UPLC BEH C18 1.7um, 2.1mm ID X 30mm L or Waters XBridge C18 3.5um, 2.1mm ID X
50mm L. All the methods are using MeCN/H20 gradients. MeCN and H20 contain either 0.1% Formic Acid
or NH3 (10mM). ative LCMS: Column used, Waters XBridge Prep C18 Sum ODB 30mm ID x 100mm
L. All the methods are using either MeOH/HZO or MeCN/H20 gradients. MeOH, MeCN and H20 contain
either 0.1% Formic Acid or 0.1 % Diethylamine. Analytic chiral LC: Column used, Chiralpak IA 5 um 250 x
4.6 mm. Microwave heating was med with a Biotage Initiator.
Table I: List of abbreviations used in the mental section:
r‘ microliter DMAP 4-Dimethylaminopyridine
DME D1methoxyethane
Acetic acid
DMF N,N-dimethylformamide
g5 aqueous
DMSO Dimethylsulfoxide
ATP ine 5 '-Triphosphate
Dulbecco's Phosphate-Buffered
2,2 -b1s(d1phenylphosph1n0)-1 ,1 - DPBS
BINAP Saline
binaphthyl
1,1’-
Boc tert-Butyloxy—carbonyl DPPF
phenylphosphino)ferrocene
BocZO Di-lerZ-butyl dicarbonate
EtOAc Ethyl acetate
br s broad singlet
EtZO Diethyl ether
Calcd calculated
equivalent
Cat. Catalytic amount
gram
doublet
guanosine 5'—O-[gamma-
Doublet of doublet thiO]triphosphate
hour
DCC N,N’-Dicyclohexylcarbodiimide
DCE 1,2-Dichloroethane Heptane
DCM Dichloromethane High-performance liquid
chromatography
DIAD Diisopropyl azodicarboxylate
1sopropanol.
DIPEA N,N—diisopropylethylamine
Diisopropyl ether
2012/076275
KHMDS Potassium hexamethyldisilazane obsd observed
Liquid Chromatography- Mass Pd(OAc)2 Palladium(H) acetate
LCMS
Spectrometry
Tetrakis(triphenylphosphine)palladi
Pd(PPh3)4
Liter um(0)
multiplet Pd/C Palladium on Carbon 10%
Methanol ppm part-per-million
Acetonitrile quadruplet
Methyl iodide 76%H8 revolutions per minute
Methyl ethyl ketone Room ature
(IQ milligram retention time
minute 2-Dicyclohexylphosphino-2',6'-di-i-
propoxy- 1 ,1 '-biphenyl
milliliter
millimole
mE Starting material
mass spectrometry
Scintillation proximity assay
Z2 Molecular weight
Solid phase extraction
Molecular weight calculated
(calc) sodiumtriacetoxyborohydride
MW (obs) Molecular weight observed II triplet
Nicotinamide adenine dinucleotide E Tetra-n-butylammonium fluoride
NADP
ylamine
%i Non-Essential Amino Acid
Trifluoroacetic acid
N—Methyl-Z-pyrrolidone
Tetrahydrofuran
Nuclear Magnetic Resonnance
Thin layer chromatography
l Synthetic Method
ediates
The intermediates to prepare the compounds according to the invention can be produced according
to the following schemes.
J::l\/\ 0
\ J::l\/\ JL
\0 NH2 0 fl NH2
Intermediate 1 Intermediate 2
CI 1
4L I J::l\/\ 0
O N <— v0 NJLNH v JL
/ o N NH2
O/\/ 0M0 H
Intermediate 5 Intermediate 4 Intermediate 3
O/fi 0/fi 0/fi
kfo K/O kgo
N / N/ N / a ' I I
N oéLN 4kN Qmif
OH O "0
compound 118 Intermediate 6 Intermediate 9
0/} 0/} o
KIO K10 KIO
O O O
N / N / N/
| A I I
N o N N 0.. k':
OH 0' "0
compound 117 Intermediate 7 Intermediate 10
0N 0N ofi
Y Y Y
o O o
N’ N/ N’
I I
N o N oél‘N I o,
OH 0' -
compound 1 ediate 8 Intermediate 11
Intermediate 1: [2-(3-methoxy-phenyl)-ethyl]-urea
A solution of 3-methoxyphenethylamine (100 g, 661.3 mmol, 1 eq.), urea (157.3 g, 2619.0 mmol,
4 eq.), AcOH (36 mL) and aq. HCl (12 mL) in H20 (800 mL) was heated under reflux for 5 days. The
reaction mixture was cooled to RT, the solid was d off, washed with water and dried to afford
intermediate 1.
(1H, CDC13) 5 (ppm): 7.24 (1H, t), 6.82-6.77 (3H, m), 5.10 (1H, br s), 4.52 (2H, br), 3.81 (1H, s), 3.42 (2H, br
t), 2.80 (2H, t)
Intermediate 2: [2-(3-hydr0xy-phenyl)—ethyl]-urea
A solution of ediate 1 (72 g, 370.7 mmol) in concentrated HBr (500 mL) was heated under
reflux overnight. The reaction mixture was brought to basic pH by addition of NaHC03 and extracted with
EtOAc. The organic layer was dried over MgSO4 and concentrated under vacuum to afford ediate 2.
(1H, MeOD-d4) 5 (ppm): 7.15 (1H, t), 6.76-6.68 (3H, m), 3.40-3.36 (2H, t), 2.77—2.74 (2H, t)
Intermediate 3: [2-(3-allyloxy-phenyl)-ethyl]-urea
To a solution of intermediate 2 (45 g, 249.7 mol, 1 eq.) and K2C03 (103.5 g, 749.1 mmol, 3 eq.)
in anhydrous DMF (300 mL) under a en atmosphere, was added allylbromide (50.5 mL, 499.4 mol, 2
eq.). The reaction e was stirred for 2.5 days, then DMF was evaporated to dryness. The residue was
dissolved in EtOAc, washed with saturated Na2C03, brine, dried over MgSO4 and trated under
vacuum to afford intermediate 3.
(1H, 4) 6 (ppm): 7.24 (1H, t), 6.87-6.81 (3H, m), 6.16-6.06 (1H, m), 5.45 (1H, dd), 5.29 (1H, dd),
4.59-4.57 (2H, m), 3.38 (2H, t), 2.80 (2H, t)
Intermediate 4: 1-[2-(3-allyloxy-phenyl)-ethyl]-pyrimidine-2,4,6-tri0ne
Sodium (20.06 g, 872 mmol, 1 eq.) was dissolved in EtOH (1.4 L). Diethyl malonate (132.4 mL,
872 mol, 1 eq.) was added and the reaction e was heated under reflux for 1h. Intermediate 3 (96 g,
436 mmol, 0.5 eq.) in EtOH (300 mL) was added and the reaction mixture was heated under reflux for 12 h.
The reaction was cooled to RT, 1N aq. HCl was added and the precipitate was filtered, washed with water
and dried to afford intermediate 4.
(1H, CDC13) 8 (ppm): 8.40 (1H, br s), 7.25 (1H, t), 6.88-6.82 (3H, m), 6.14-6.04 (1H, m), 5.45 (1H, dd), 5.32
(1H, dd), 4.58-4.56 (2H, m), 4.13 (2H, t), 3.64 (2H, s), 2.92 (2H, t)
MW (calcd): 288.3; MW (obsd): 289.3 (M + 1)
Intermediate 5: 9-allyloxychlor0-6,7-dihydr0-pyrimid0[6,1-a]isoquinolin0ne
A solution of intermediate 4 (20 g, 69.4 mol, 1 eq.) in POC13 (150 mL) was stirred at 50°C for 3
days. POC13 was evaporated under vacuum and the residue was dissolved in DCM and quenched with
saturated NaHCOg. The organic layer was washed with water, dried over MgSO4 and concentrated to afford
intermediate 5.
(1H, CDC13) 6 (ppm): 7.71 (2H, d), 6.97 (1H, dd), 6.86 (1H, d), 6.71 (1H, s), 6.13-6.04 (1H, m), 5.47 (1H,
dd), 5.36 (1H, dd), 4.67-4.65 (2H, m), 4.27 (2H, t), 3.05 (2H, t)
MW (calcd): 288.7; MW (obsd): 289.3 (M+1)
General methods
General method A:
/\O / ’
N NaH N A | |
O N O N
To a solution of NaH (2 eq., 60% in mineral oil) in anhydrous DCM at 0°C, is added 2-
hydroxymethyl-[1,4]dioxane (2 eq.) with the appropriate chirality, after 15 min, intermediate 5 (1 eq.) is
added at 0°C, and the reaction is stirred at RT until completion. Saturated NH4Cl is added to the reaction
mixture, the organic layer is washed with water, dried over MgSO4 and concentrated. The desired product is
purified by flash chromatography on silica gel.
2-Hydroxymethyl-[1,4]dioxane, (R) 2-hydroxymethyl-[1,4]dioxane and (S) 2-hydroxymethyl-
[1,4]dioxane are commercially ble or can easily be prepared [Young Kim er al ; Bioorganic &
Medicinal Chemistry 15 (2007) 2667—2679].
Illustrative sis of general method A:
Compound 118: 9-allyloxy((S)[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-
4-one
A on of (R) 2-hydroxymethyl—[1,4]dioxane (56.6 g, 479 mmol, 2 eq.) and NaH (19.9 g, 479
mol, 2 eq., 60% in mineral oil) in anhydrous DCM (300 mL) was stirred for 30 min at 0°C. Intermediate 5
(69.2 g, 240 mol, 1 eq.) in solution in anhydrous DCM (700 mL) was added at 0°C. The on e
was stirred for 2 h. Saturated NH4C1 was added, the organic layer was washed with water, dried over MgSO4
and ated to dryness. The crude product was d by flash chromatography on silica gel
(MeOH/DCM) to afford compound 118.
(H, CDC13) 8 (ppm): 7.66 (1H, d), 6.94 (1H, dd), 6.83 (1H, d), 6.32 (1H, s), 6.15-6.03 (1H, m), 5.47 (1H,
dd), 5.37 (1H, dd), 4.65-4.63 (2H, m), 4.51-4.39 (2H, m), 4.23 (2H,t), 4.06-3.98 (1H, m), 3.92-3.47 (6H, m),
3.01 (2H, t)
Compound 1: 9-allyloxy([1,4]dioxan—2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolinone
Compound 1 was prepared using general method A starting from 2-hydr0xymethyl-[1,4]di0xane.
(1H, CDC13) 6 (ppm): 7.66 (1H, d), 6.94 (1H, dd), 6.83 (1H, d), 6.32 (1H, s), 6.11-6.04 (1H, m), 5.47 (1H,
dd), 5.35 (1H, dd), 4.65-4.63 (2H, m), 4.491-4.40 (2H, m), 4.22 (2H, t), 4.02-3.99 (1H, m), .46 (6H,
m), 3.00 (2H, t)
MW (calcd): 370.4; MW (obsd): 371.4 (M+1)
Compound 117: loxy((R)[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-
4-one
[00221] nd 117 was prepared using general method A starting from (S) 2-hydr0xymethyl-
[1,4]dioxane.
(1H, CDC13) 5 (ppm): 7.66 (1H, d), 6.94 (1H, dd), 6.83 (1H, d), 6.31 (1H, s), 6.12-6.04 (1H, m), 5.49 (1H,
dd), 5.36 (1H, dd), 4.65-4.63 (2H, m), 4.50-4.42 (2H, m), 4.23 (2H, t), 4.04-4.00 (1H, m), 3.91-3.50 (6H, m),
3.01 (2H, t)
MW (calcd): 370.4; MW (obsd): 371.2 (M+1)
General method B:
0 (150fi
o/ 0/
j]: I Pd(PPh3)4, K2C03 N/
—> |
O N
O N
To a suspension 0fc0mp0und 1, 117 or 118 (1 eq.) in a mixture of DCM/MeOH (1/1) is added
K2CO3 (2 eq.) and Pd(PPh3)4 (0.05 eq.). The reaction e is degassed before stirring at RT. After
completion, water is added to the reaction mixture and the s layer is separated. The pH of the aqueous
solution is adjusted to pH 1 with 2M aq. HCl. The precipitate is filtered off, washed with water and dried to
afford intermediate 6, 7 0r 8.
Illustrative sis of general method B:
Intermediate 6: 2-((S)[1,4]dioxanylmethoxy)hydroxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-
4-one
To a suspension of compound 118 (31.15 g, 84.2 mmol, 1 eq.) in a mixture of OH (1/ 1,
800 mL) was added K2C03 (23.2 g, 138.2 mol, 2 eq.) and Pd(PPh3)4 (4.86 g, 4.21 mmol, 0.05 eq.). The
reaction mixture was stirred at RT for 2 h. Water (800 mL) was added, and the aqueous layer was separated.
The pH of the aqueous solution is adjusted to pH 1 with 2 M aq. HCl. The precipitate was filtered off, washed
with water and dried to afford intermediate 6.
(1H, DMSO-d6) 6 (ppm): 7.84 (1H, d), 6.77 (1H, dd), 6.74 (1H, d), 6.45 (1H, s), 4.25-4.23 (2H, m), 3.99 (2H,
t), 3.87-3.75 (3H, m), 3.68-3.58 (2H, m), 3.52-3.46 (1H, m), 3.40-3.30 (1H, m), 2.91 (2H, t)
MW ): 330.4; MW : 331.3 (M+1)
Intermediate 7: 2-((R)[1,4]dioxanylmeth0xy)hydr0xy-6,7-dihydr0-pyrimid0[6,1-a]is0quin01in-
4-0ne
Intermediate 7 was prepared using l method B starting from nd 117 .
(1H, DMSO-d6) 8 (ppm): 7.83 (1H, d), 6.77 (1H, dd), 6.74 (1H, d), 6.44 (1H, s), 4.27-4.20 (2H, m), 3.98 (2H,
t), .74 (3H, m), 3.68-3.57 (2H, m), 3.52-3.46 (1H, m), 3.40-3.34 (1H, m), 2.91 (2H, t)
Intermediate 8: 2-([1,4]dioxanylmeth0xy)hydr0xy-6,7-dihydr0-pyrimid0 [6,1-a]is0quinolin0ne
Intermediate 8 was prepared using general method B starting from compound 1.
(1H, DMSO-d6) 6 (ppm): 7.84 (1H, d), 6.77 (1H, dd), 6.74 (1H, d), 6.45 (1H, s), .20 (2H, m); 3.99 (2H,
t), .73 (3H, m), 3.68-3.58 (2H, m), 3.52-3.46 (1H, m), 3.40-3.34 (1H, m), 2.91 (2H, t)
MW (calcd): 330.4; MW (obsd): 331.0 (M+1)
General method C:
[00226] A solution of intermediate 6, 7 or 8 (1 eq.), N—phenyl-bis(trifluoromethanesulfonimide) (1.2 eq.)
and Et3N (1.3 eq.) in DCM under nitrogen is stirred at RT until completion. The reaction e is
concentrated and the crude is purified by crystallization from iPrOH to afford intermediate 9, 10 or 11.
Illustrative synthesis of general method C:
Intermediate 9: trifluoro-methanesulfonic acid 2-((S)[1,4]dioxanylmeth0xy)0x0-6,7-dihydr0-
4H-pyrimid0 [6,1-a]is0quinolinyl ester
A solution of intermediate 6, (24 g, 72.7 mol, 1 eq.), N—phenyl-bis(trifluoromethanesulfonimide)
(31.15 g, 87.2 mmol, 1.2 eq.) and Et3N (13.2 mL, 94.4 mmol, 1.3 eq.) in DCM (700 mL) under a nitrogen
atmosphere is stirred at RT overnight. The reaction mixture is concentrated. The crude is taken in iPrOH (75
mL) heated under reflux and cool to RT. After two days at RT, the solid is filtered off and dried to afford
intermediate 9.
(1H, CDC13) 8 (ppm): 7.83 (1H, d), 7.35 (1H, dd), 7.29 (1H, d), 6.41 (1H, s), 4.51-4.42 (2H, m), 4.28 (2H, t),
4.06-4.01 (1H, m), 3.89-3.69 (5H, m), 3.52 (1H, m), 3.11 (2H, t)
Intermediate 10: trifluoro-methanesulfonic acid 2-((R)[1,4]dioxanylmethoxy)oxo-6,7-dihydro-
4H-pyrimido [6,1-a]isoquinolinyl ester
Intermediate 10 was prepared using general method C starting from intermediate 7.
(H, CDC13) 8 (ppm): 7.83 (1H, d), 7.34 (1H, dd), 7.29 (1H, d), 6.41 (1H, s), 4.51-4.41 (2H, m),
4.28 (2H, t), 4.05-4.00 (1H, m), 3.91-3.66 (5H, m), 3.52 (1H, t), 3.11 (2H, t)
Intermediate 11: trifluoro-methanesulfonic acid 2-([1,4]dioxanylmethoxy)oxo-6,7-dihydro-4H-
pyrimido [6,1-a]isoquinolinyl ester
Intermediate 11 was prepared using l method C starting from intermediate 8.
(1H, DMSO-d6) 5 (ppm): 8.21 (1H, d), 7.65 (1H, d), 7.54 (1H, dd), 6.75 (1H, s), 4.28-4.26 (2H, m), 4.04 (2H,
t), 3.90-3.84 (1H, m), 3.81-3.75 (2H, m), 3.68-3.58 (2H, m), 3.53-3.47 (1H, m), .36 (1H, m), 3.10 (t,
MW (calcd): 462.4; MW (obsd): 463.3 (M+1)
0/0 O/\ o/\
K/O KKO go
o’ 0’5 o’
| N /
| N /
A F |
O N Q. kl: Step 1 CAN Step 2 CAN
.8" F
O _>
o N |
Intermediate 9 Intermediate 12 Intermediate 13
ediate 13: 9-amino((S)[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin
one hydrochloride
Step I .' 9-(Benzhydrylidene-amin0)((S)-I -[I,4]dioxan-Z-ylmethoxy)-6, 7—dihydr0-pyrimid0[6,1 -
ajisoquinolin0ne (Intermediate 12)
] A solution of intermediate 9 (1 g, 2.16 mol, 1 eq.), )2 (24 mg, 0.11 mmol 0.05 eq.),
CsZC03 (2.11 g, 6.48 mmol, 3 eq.) BINAP (134 mg, 0.21 mmol, 0.1 eq.) and benzophenonimine (587 mg,
3.24 mmol, 1.5 eq.) in toluene (20 mL) was heated at 150°C in a microwave for 45 min. The solvent was
evaporated to dryness and the crude mixture was taken in water and extracted with EtOAc. The organic layer
was dried over MgSO4 and concentrated under vacuum. 9-(Benzhydrylidene-amino)((S)[1,4]dioxan
ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolinone intermediate 12 was obtained after purification by
flash chromatography on silica gel and ately used in next step.
Step 2: 9-amin0((S)-I -[I,4]di0xanylmeth0xy)-6, 7—dihydr0-pyrimid0[6, I -a]is0quinolin0ne
hydrochloride (Intermediate 1 3)
] To a solution of intermediate 12 in a minimum of DCM/ Et20 was added HCl 2N in EtZO (4 mL).
The precipitate was filtered off and dried to afford intermediate 13.
(H, DMSO-d6) 6 (ppm): 7.82 (1H, d), 7.45 (3H, br), 6.68 (1H, d), 6.67 (1H, s), 6.51 (1H, s), 4.32 (2H, d),
3.99 (2H, t), 3.90-3.84 (1H, m), 3.82-3.35 (6H, m), 2.88 (2H, t)
MW (calcd): 329.4; MW (obsd): 330.2 (M+1)
General method D:
/ + BrVBF3K _,
K K,OVBF3K
The corresponding l (2 eq.) is added to a solution of NaH (2 eq., 60% in mineral oil) in
THF at 0 °C. The reaction is warmed to RT for 30 min then cooled again at 0 °C. Bromo
methyltrifluoroborate (1 eq.) is added to the reaction in one portion and the mixture is stirred at RT from few
hours to 3 days (monitoring by R). The reaction is quenched with a solution of KHFZ (1.5 M, 3 eq.)
and the mixture is evaporated to dryness. The residue is suspended in acetone, the inorganics are filtered off
and the filtrate is evaporated to dryness. The residue is suspended in a minimum amount of acetone, EtzO is
added and the product is obtained by filtration.
rative s nthesis 0f eneral method D:
Intermediate 14: tetrahydro-2H-pyran01-methyl trifluoroborate
(5 KBF O
BrVBFsK 3V
Intermediate 14
[00234] Tetrahydro-pyranol (152 mg, 1.49 mmol, 2 eq.) was added to a solution ofNaH (60 mg, 1.49
mol, 2 eq., 60% in mineral oil) in THF (4 mL) at 0 °C. The reaction was warmed to RT for 30 min then
cooled again at 0 °C. Bromo methyltrifluoroborate (150 mg, 0.75 mol, 1 eq.) was added to the reaction in
one portion and the mixture was stirred at RT for 1 day (monitoring by 19F-NMR). The on was
ed with a solution of KHFZ (1.5 mL, 1.5 M, 3 eq.) and the mixture was evaporated to dryness. The
residue was suspended in acetone, the nics were filtered off and the filtrate was evaporated to dryness.
The residue was ded in a minimum amount of acetone (1.5 mL), and EtZO (6 mL) was added.
Intermediate 14 was obtained by filtration.
(1H, DMSO-d6) 5ppm 3.78 (2 H, d), 3.31 - 3.21 (2 H, m), 3.18 - 3.08 (1 H, m), 2.50 - 2.45 (2 H, m), 1.86 -
1.74 (2 H, m), 1.34 - 1.19 (2 H, m)
Intermediate 15: potassium oxetanemethyltrifluoroborate
b KBF O
BF3KVBr 3V v
Intermediate 15
Intermediate 15 was prepared Via general method D with oxetanol (the trifluoroborate reagent
was recovered with the inorganics rather than the e).
(1H, DMSO-d6) 5 ppm 4.56 (2 H, s), 4.32 (3 H, d), 2.40 (2 H, (1)
Intermediate 16: potassium (3-methylmethyloxy-oxetane-methyltrifluoroborate
+ HO\/€/o r
_ \/€/o
Intermediate 16
Intermediate 16 was prepared Via general method D with (3-methyloxetanyl) methanol (the
trifluoroborate reagent was recovered with the nics rather than the filtrate).
(1H, 6) 5 ppm 4.34 (2 H, d), 4.14 (2 H, d), 3.26 (2 H, s), 2.59 _ 2.52 (2 H, m), 1.19 (3 H, 5)
Intermediate 17: potassium 2,2-dimethyl-propyloxy-methyltrifluoroborate
BF3KVBr
+ [40% I KBF3\/O\/¥
Intermediate 17
[00237] Intermediate 17 was prepared Via general method D with 2,2-dimethyl—pr0panol.
(1H, DMSO-d6) 5 ppm 2.88 (2 H, s), 2.51 - 2.45 (2 H, m), 0.83 (9 H, 5)
Intermediate 18: potassium cyclopropylmethoxy-methyltrifluoroborate
BF3KVBF
+ HO\/A KBF3VO\/A
Intermediate 18
[00238] Intermediate 18 was prepared Via general method D wOith cyclopropyl-methanol.
(1H, DMSO-d6) 5 ppm 3.00 (2 H, d), 2.46 (2 H, d), 1.00 - 0.82 (1 H, m), 0.46 - 0.31 (2 H, m), 0.13 - 0.00 (2
H, m)
Intermediate 19: cyclopentylmethoxy-methyltrifluor0b0rate
BFsKVBr
+ HO\/O , KBF3VO\/O
Intermediate 19
] Intermediate 19 was prepared Via general method D with cyclopentyl-methanol.
(1H, 6) 5 ppm 3.04 (2 H, d), 2.46 (2 H, d), 2.08 — 1.94 (1 H, m), 1.47 (6 H, br. s.), 1.07 - 1.22 (2 H,
Intermediate 20: potassium 2-cyclopropyl—ethyl—trifluor0b0rate
V/\/Br V/\/BF3K
Intermediate 20
A 2-neck round bottom flask equipped with a reflux condenser and an addition funnel was
charged with Mg (193 mg, 8.05 mol, 3 eq.) and EtZO (1 mL) under N2. One drop of neat (2-bromo-ethyl)-
cyclopropane was added followed by two drops of dibromoethane. Once the 1St s appeared, (2-bromoethyl
)-cyclopropane (400 mg, 2.68 mmol, 1 eq.) in EtZO (5 mL) was added dropwise. Upon completion of
the addition, the resulting suspension was stirred at RT for 1 h. In a separate flask, purged with N2, a solution
made of 3 (0.45 mL, 4.02 mmol, 1.5 eq.) in THF (6 mL) was cooled to -78 °C. To this solution, the 2-
cyclopropyl—ethyl magnesium e suspension was added dropwise Via a double ended needle. The
e was allowed to stir for 1 h at -78 °C and then was warmed to RT for 1 h. After cooling the mixture to
0 °C, a saturated aqueous on of KHF2 (2.5 mL, 4.5 M, 4.1 eq.) was added dropwise and the reaction
mixture was allowed to warm to RT. After 30 min, the solution was concentrated in-vacuo. The dried solids
were triturated with hot acetone and filtered to remove inorganic salts. The resulting filtrate was concentrated
and the solid residue was triturated with EtZO. Potassium 2-cyclopropyl-ethyl-trifluoroborate was filtered and
dried in-vacuo.
(1H, DMSO-d6) 5 ppm 1.07 — 0.92 (2 H, m), 0.66 - 0.53 (1 H, m), 0.27 - 0.21 (2 H, m), 0.067 - -0.07 (2 H, m),
-0.117 - -0.17 (2 H, m)
General method E:
o/fi o/fi
3° 3°
0 O
N/l —’ N/l
O N O N
OTf Z
Intermediate 9, 10, 11
A vial is charged with intermediate 9, 10 or 11 (1 eq.), the appropriate boronic acid, boronic ester
or potassium trifluoroborate (4.4 eq.), Cs2C03 (2.6 eq.), (DPPF)PdC12.DCM (0.05 eq.), in oxane/H20
(10/1 , v/v), and the mixture is degassed with N2. The vial is sealed and heated at 80 °C. When the reaction is
complete, the vial is cooled to RT and the reaction is either worked up or volatiles are evaporated under
. The product is then obtained after purification by either flash tography on silica gel,
preparative TLC or preparative HPLC-MS.
Illustrative s nthesis of eneral method E:
Compound 2: 2-([1,4]dioxanylmethoxy)pyridinyl-6,7-dihydro-pyrimido [6,1-a]isoquinolinone
oN oN
° 5°
0 O
O N O N
OTf \
Intermediate 11 Compound 2
A vial was charged with intermediate 11 (84 mg, 0.074 mol, 1 eq.), pyridine-3 -boronic acid (40
mg, 0.327 mmol, 4.4 eq.), Cs2C03 (62 mg, 0.190 mmol, 2.6 eq.), PdC12.DCM (3.3 mg, 0.004 mmol,
0.05 eq.), in 1,4-dioxane (1 mL) and H20 (0.1 mL), and the mixture was degassed with N2. The vial was
sealed and heated at 80 °C. After 1h, the vial was cooled to RT and volatiles were evaporated under vacuum.
The residue was then purified by flash tography on silica gel, eluting with 7.5% MeOH/DCM to
afford compound 2.
(1H, CDC13) 5 ppm 8.89 (1 H, s), 8.67 (1 H, d), 7.93 (1 H, d), 7.82 (1 H, d), 7.61 (1 H, d), 7.53 (1 H, s), 7.43
(1 H, dd), 6.43 (1 H, s), 4.51 - 4.37 (2 H, m), 4.26 (2 H, t), 3.99 (1 H, m), 3.92 - 3.60 (5 H, m), 3.49 (1 H, m),
3.10 (2 H, t)
General method F:
o/fi o/fi
3° 3°
0 O
N / —> N /
I I
O N O N
OH O’Y
ediate 6, 7, 8
A solution of intermediate 6, 7, 0r 8 (1 eq.), the appropriate alkylating agent (1.5 eq.), K2C03 (2
eq.), KI (1 eq.) in MEK is heated at 80 °C. When the reaction is complete, the volatiles are evaporated to
dryness and the residue is purified by flash chromatography on silica gel to give the desired product.
Illustrative s nthesis of eneral method F:
Compound 8: 2-([1,4] dioxanylmethoxy)(oxazolylmethoxy)-6,7-dihydro-pyrimido [6,1-
uinolinone
ON ON
T 5°
0 O
A A
O N O N
OH O
Intermediate 8
Compound 8
A solution of intermediate 8 (40 mg, 0.12 mol, 1 eq.), 2-ch10r0methy10xazole (21 mg, 0.18
mmol, 1.5 eq.), K2CO3 (33 mg, 0.24 mmol, 2 eq.), KI (20 mg, 0.12 mmol, 1 eq.) in MEK (2 mL) was heated
at 80 °C for 16 h. The reaction was evaporated to dryness and the residue was d by flash
chromatography on silica gel, eluting with 4% CM to give compound 8.
(1H, CDC13) 6 ppm 7.72 (1 H, d), 7.68 - 7.60 (1 H, m), 7.18 (1 H, d), 7.02 (1 H, dd), 6.93 (1 H, d), 6.28 (1 H,
s), 5.23 (2 H, s), 4.49 — 3.94 (1 H, m), 3.89
- 4.33 (2 H, m), 4.19 (2 H, t), 4.02 - 3.61 (5 H, m), 3.48 (1 H, dd),
2.98 (2 H, t)
MW (calcd): 411.4; MW (obsd): 412.4 (M+1)
General method G:
3° 3°
0 O
O N OAN
OTf §
Intermediate 9, 10, 11
Intermediate 9, 10, 11 (1 eq.) is dissolved in DMF, the appropriate alkyne (3 eq.) is added
followed by TEA (3.5 eq.), and the e is ed. Pd(PPh3)3C12 (0.05 eq.) is added with CuI (0.2 eq.)
and the reaction mixture is heated at 80 °C. When the reaction is gone to completion, it is cooled to RT and
either worked up or volatiles are evaporated to dryness. The product is then obtained after purification by
either flash chromatography on silica gel, preparative TLC or ative HPLC-MS.
Illustrative s nthesis of eneral method G:
Compound 16: 2-([1,4] dioxan—2-ylmeth0xy)—9-(1-methyl-1H-imidazol—2-ylethynyl)-6,7-dihydr0-
pyrimido [6,1-a]isoquinolin0ne
ON ON
O 0
j: —’
| j: |
O N O N
OTf % N
Intermediate 11 Compound 16
Intermediate 11 (1.4 g, 3.03 mol, 1 eq.) was ved in DMF (20 mL), 5-ethynylmethyl-1H-
imidazole (0.92 mL, 9.09 mmol, 3 eq.) was added ed by TEA (1.48 mL, 10.61 mmol, 3.5 eq.). The
mixture was degassed and 3)3C12 (106 mg, 0.15 mmol, 0.05 eq.) was added with CuI (115 mg, 0.61
mmol, 0.2 eq.). The reaction mixture was heated at 80 °C for 16 h. The reaction was cooled to RT and
quenched with brine, the mixture was then extracted with EtOAc. The organic layer was dried over MgSO4
and the solvent was evaporated under vacuum. The crude product was then purified by flash chromatography
on silica gel, eluting from 0 to 5% MeOH/DCM to give compound 16.
WO 92791
(1H, CDC13) 5 ppm 7.73 (1 H, d), 7.57 - 7.50 (2 H, m), 7.48 - 7.45 (1 H, m), 7.42 (1 H, d), 6.42 (1 H,
s), 4.53 - 4.39 (2 H, m), 4.28 - 4.23 (2 H, m), 4.07 - 3.97 (1 H, m), 3.94 - 3.64 (8 H, m), 3.52 (1 H,
dd), 3.06 (2 H, t)
MW (calcd): 418.4; MW (obsd): 419.4 (M+1)
General method H:
o/fi o/fi
:0 30
O 0
oil | —’ o”; I
% v % v
OH 0\
tBuOK (3 eq.) is added to a solution of the corresponding acetylenic alcohol (1 eq.) in THF, Mel
(10 eq.) is then added and the reaction is d at RT. When the reaction has gone to completion, the
reaction mixture is filtered and the filtrate is evaporated to dryness. Product is obtained after ation by
preparative TLC.
Illustrative s nthesis 0f eneral method H:
nd 110: 2-([1,4]dioxan-Z-ylmeth0xy)(3-meth0xymethyl-pentynyl)-6,7-dihydr0-
pyrimido [6,1-a]isoquinolin0ne
o/\ o/\
80 50
O O
N / N /
DAN | —> CAN |
% %
OH 0\
Compound 91 Compound 110
tBuOK (5.19 mg, 0.046 mmol, 0.95 eq.) was added to a solution of compound 90 (20 mg, 0.049
mmol, 1 eq.) in THF (2 mL), Mel (0.030 mL, 0.487 mmol, 10 eq.) was then added and the reaction was
d at RT for 16 h. Some more tBuOK (11 mg, 0.097 mmol, 2 eq.) was added and the reaction was stirred
for an extra day. The reaction mixture was filtered and the filtrate was evaporated to dryness. The crude
product was purified by preparative TLC eluting with 2% MeOH/DCM to yield compound 110.
(1H, CDC13) 6 ppm 7.70 - 7.60 (1 H, d), 7.50 - 7.42 (1 H, d), 7.39 (1 H, s), 6.37 (1 H, s), 4.50 - 4.35 (2 H, m),
4.25 - 4.15 (2 H, m), 4.05 - 3.95 (2 H, m), 3.92 - 3.60 (5 H, m), 3.56 - 3.45 (4 H, m), 3.05 - 3.95 (2 H, m),
2.15 - 1.95 (1 H, m), 1.15 - 1 (6 H, t)
MW (calcd): 424.5; MW (obsd): 425.2 (M+1)
General method I:
:0 o
0 Q
Axl _. N’|
O N
O N
%U U
A vial is charged with Pd/C (10% w/w) and a solution of the appropriate alkyne (1 eq.) in MeOH
is added. The system is purged with N2 before being filled with H2 then the reaction is stirred at RT until
completion. The reaction is filtered through Celite and the filtrate is evaporated to dryness. Clean product is
obtained after purification by either flash chromatography on silica gel, preparative TLC or preparative
HPLC-MS.
rative s s of eneral method I:
Compound 116: 2-([1,4]di0xanylmeth0xy)(3-hydr0xypyridin—3-yl-pr0pyl)-6,7-dihydr0-
do [6,1-a]isoquinolin0ne
o90
oél‘N I N/
—> A I
O N /
% | \ IN
Compound 108 Compound 116
A vial was charged with Pd/C (9 mg, 10% w/w) and a solution of compound 108 (87 mg 0.20
mol, 1 eq.) in MeOH (10 mL) was added. The system was purged with N2 before being filled with H2 then
the reaction was d for 16 h at RT. The reaction was filtered through Celite and the filtrate was
evaporated to s. The crude product was purified by preparative HPLC-MS to give compound 116.
WO 92791
(1H, CDC13) 6 ppm 8.60 - 8.48 (2 H, m), 7.73 (1 H, d), 7.61 (1 H, d), 7.30 (1 H, dd), 7.20 (1 H, d), 7.12 (1 H,
s), 6.35 (1 H, s), 4.77 (1 H, dd), 4.47 - 4.33 (2 H, m), 4.18 (2 H, t), 3.97 (1 H, m), 3.90 - 3.60 (5 H, m), 3.48
(1 H, t), 2.96 (2 H, t), 2.90 — 1.98 (1 H, m), 1.38 (1 H, t)
- 2.70 (2 H, m), 2.15 (1 H, m), 2.10
MW (calcd): 449.5; MW (obsd): 450.1 (M+1)
General method J:
O; 0;
j: | —> I|
o N o N
NH2.HC| H’T
ediate 13
Intermediate 13 (1 eq.) is dissolved in DMF, the appropriate aldehyde (4 eq.) is added followed by
KOH (1 eq.). The reaction is stirred for 15 min at RT before STAB (10 eq.) is added, the mixture is then
stirred at RT until completion of the reaction. The mixture is then quenched with brine, extracted with
EtOAc, the organic layer is dried over MgSO4 and evaporated to s. cation by preparative HPLC-
MS affords the corresponding product.
Illustrative synthesis of general method J:
Compound 126: 9-(2,2-dimethyl-butylamino)—2-((S)[1,4]dioxanylmethoxy)-6,7-dihydropyrimido
[6,1-a]isoquinolinone
Co 0”
\... \.
O O
N / /
O N O N
NH .HCI
2 H/><\N
Intermediate 13 Compound 126
Intermediate 13 (50 mg, 0.14 mol, 1 eq.) was dissolved in DMF (2 mL), 2,2-dimethylbutanal (56
mg, 0.56 mmol, 4 eq.) was added followed by KOH (8 mg, 0.14 mol, 1 eq.). The reaction was stirred for 15
min at RT before STAB (297 mg, 1.40 mmol, 10 eq.) was added, the mixture was then stirred for 2 days at
RT. The on was quenched with brine and the mixture was extracted with EtOAc. The organic layer was
dried over MgSO4 and evaporated to dryness. The crude product was purified by preparative HPLC-MS to
give compound 126.
(H, CDC13) 6 ppm 7.50 (1 H, d), 6.63 (1 H, dd), 6.48 (1 H, s), 6.21 (1 H, s), 4.47 - 4.34 (2 H, m), 4.21 - 4.14
(2 H, m), 4.01 — 3.91 (1 H, m), 3.89 - 3.60 (5 H, m), 3.48 (1 H, dd), 2.98 (2 H, s), 2.90 (2 H, t), 1.36 (2 H,
dd), 0.96 (6 H, s), 0.87 (3 H, t)
MW (calcd): 413.5; MW (obsd): 414.4 (M+1)
General method K:
05 ° 05
b0 0
o? o/E O;
I N /
1 W 1
—> /
O It / F —’ ¢
o N
N ofs/kFF o N
O \\O \\ OH \\ O\
Intermediate 9 Intermediate 15
Step I : 2-((S)-I-[I,4]di0xanylmeth0xy)(3-hydr0xy-pr0p-I-ynyl)-6, 7-dihydr0-pyrimid0[6,1-
uinolin0ne (Intermediate 15)
Intermediate 15 2-((S)[1,4]dioxanylmethoxy)(3-hydroxy-propynyl)-6,7-dihydro-
pyrimido[6,1-a]isoquinolinone was synthesised via general method E with intermediate 9 and propyn-
1-ol.
Step 2:
] Intermediate 15 (1 eq.) is dissolved in a e of THF/DMF (1/ 1), NaH (1.1 eq., 60% in mineral
oil) is added followed by the appropriate alkylating agent (1 eq.) and the reaction is stirred at 70 °C. When
the reaction has gone to completion, the mixture is worked up with brine and EtOAc, the c layer is
dried over MgSO4 and evaporated to dryness. Purification by preparative HPLC-MS es the
corresponding product.
Illustrative synthesis of l method K:
Compound 133: [1,4]dioxanylmethoxy)[3-(2-methoxy-ethoxy)-propynyl]-6,7-dihydropyrimido
[6,1-a]isoquinolinone
go O.
O/: o/
‘ N /
0%N CAN ‘
\ OH \\
O\/\O/
Intermediate 15 Compound 133
[00255] Intermediate 15 (92 mg, 0.25 mol, 1 eq.) was dissolved in a mixture of THF/DMF (6 mL, 1/ 1),
NaH (11 mg, 0.275 mmol, 1.1 eq., 60% in mineral oil) was added followed by 1-bromomethoxy—ethane
(35 mg, 0.25 mol, 1 eq.) and the reaction was stirred at RT for 16 h, then at 70 °C for 1 day. The mixture
was worked up with brine and EtOAc, the organic layer was dried over MgSO4 and ated to dryness.
The crude product was purified by preparative HPLC-MS to provide compound 133.
(1H, CDCl3) 5 ppm 7.64 (1 H, s), 7.48 - 7.40 (1 H, m), 7.40 - 7.35 (1 H, m), 6.40 - 6.34 (1 H, m), 4.47 (4 H,
s), 4.28 — 2.95 (2 H, m)
- 4.15 (1 H, m), 3.93 - 3.56 (10 H, m), 3.43 (5 H, s), 3.06
MW (calcd): 426.5; MW (obsd): 427.4 (M+1)
General method L:
o/\ o/\
K/O K/O
O; O/é
CAN —’ CAN
OH OJVI
ediate 6
To a solution of tBuOK (2.2 eq.) in DMF is added dropwise a solution of intermediate 6 (1 eq.) in
DMF at 0 °C and the mixture is stirred for 1 h. A solution of the appropriate ting agent (10 eq.) in DMF
is added dropwise to the previous solution at 0 °C, then the reaction is d at 80 °C. When the reaction has
gone to completion, the mixture is cooled to RT, quenched with water, and extracted with EtOAc. The
combined organic layers are dried over NaZSO4 and evaporated to dryness. The product is isolated by
purification by preparative TLC.
Illustrative synthesis of general method L:
Compound 158: 9-(2,2-dimethyl-propoxy)((S)[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1-
a]isoquinolinone
o O
II I'
o N —’ O N
OH 0%
Intermediate 6 Compound 158
[00257] To a solution oftBuOK (19 mg, 0.166 mmol, 1.1 eq.) in DMF (2 mL) was added dropwise a
solution of intermediate 6 (50 mg, 0.151 mol, 1 eq.) in DMF (2 mL) at 0 °C and the mixture was stirred for
1 h. A solution of 1-iodo-2,2-dimethyl—propane (0.021 mL, 0.159 mmol, 1.05 eq.) in DMF (2 mL) was added
se to the previous solution at 0 °C, then the reaction was stirred at 80 °C for 1 day. Extra reagents were
added, 1-iodo-2,2-dimethyl-propane (0.4 mL, 10 eq.) and tBuOK (19 mg, 0.166 mmol, 1.1 eq.) and the
reaction was stirred at 80 °C for one more day. The mixture was cooled to RT, quenched with water, and
extracted with EtOAc. The combined organic layers were washed with brine, dried over NaZSO4 and
ated to dryness. Compound 158 was obtained by purification by preparative TLC [DCM/MeOH, 98/2].
(1H, CDC13)6 ppm 7.70 - 7.56 (1 H, d), 6.95 - 6.85 (1 H, d), 6.80 (1 H, s), 6.28 (1 H, s), 4.50 - 4.35 (2 H, m),
4.25 - 4.10 (2 H, m), 4.05 - 3.92 (1 H, m), 3.10 - 3.57 (8 H, m), 3.55 - 3.40 (1 H, m), 3.05 - 2.90 (2 H, m),
1.05 (9H, 5).
MW (calcd): 400.5; MW (obsd): 401.2 (M+1)
Compounds of the invention
The nds according to the ion can be produced as described below.
Compound 1: 9-Allyloxy—2-([1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolinone.
] Synthesis fiJlly described above.
Compound 2: 2-([1,4]dioxanylmethoxy)-9 -pyridin-3 -yl-6,7-dihydro-pyrimido[6,1-a]isoquinolinone.
Synthesis fiJlly described above.
Compound 3: 2-([1,4]dioxanylmethoxy)-9 -pyridinyl-6,7-dihydro-pyrimido[6,1-a]isoquinolinone.
This compound is ed via general method E using intermediate 11 and pyridineboronic
acid.
Compound 4: 2-[2-([1,4]dioxan-Z-ylmethoxy)0x0-6,7-dihydr0-4H-pyrimid0[6,1-a]is0quinolin-9 -yl] -
benzonitrile.
This compound is prepared Via general method E using intermediate 11 and 2-
cyanophenylboronic acid.
Compound 5: 3 -[2-([1,4]dioxan-Z-ylmeth0xy)0x0-6,7-dihydr0-4H-pyrimid0[6,1-a]is0quinolin-9 -yl] -
benzonitrile.
This compound is prepared Via general method E using intermediate 11 and 3-
cyanophenylboronic acid.
Compound 6: 4-[2-([1,4]dioxan-Z-ylmethoxy)0x0-6,7-dihydr0-4H-pyrimid0[6,1-a]is0quinolin-9 -yl] -
benzonitrile.
This compound is prepared Via general method E using intermediate 11 and 4-
cyanophenylboronic acid.
Compound 7: ,4]dioxan-Z-ylmethoxy)—4-0x0-6,7-dihydr0-4H-pyrimid0[6,1-a]is0quinolinyloxy]-
acetonitrile.
This compound is prepared Via general method F using intermediate 8 and bromo-acetonitrile, K1
was not used in the ment.
nd 8: 2-([1,4]di0xanylmeth0xy)(0xazolylmeth0xy)-6,7-dihydr0-pyrimid0[6,1-
a]is0quinolin0ne.
] Synthesis fiJlly described above.
Compound 9: 2-([1 ,4]di0xanylmeth0xy)—9-(pyridinylmeth0xy)-6,7 -dihydr0-pyrimid0 [6,1 -
a]is0quinolin0ne.
] This compound is ed Via general method F using intermediate 8 and pyridin-Z-yl-methanol
hydrochloride.
Compound 10: 9-(3 ,5 -dichlor0-phenyl)—2-([1,4]dioxan-Z-ylmethoxy)-6,7 -dihydro-pyrimid0 [6,1 -
a]is0quinolin0ne.
This compound is prepared Via general method E using intermediate 11 and 3,5-
dichlorophenylboronic acid.
Compound 11: 9-benzofuranyl([1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin
one.
] This compound is prepared via general method E using ediate 11 and 1-benzofuran
ylboronic acid.
Compound 12: 2-[2-([1,4]dioxanylmethoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolinyl]-
indole-l-carboxylic acid tert-butyl ester.
This nd is prepared via general method E using intermediate 11 and t-
butoxycarbonyl)- 1 H-indolylboronic acid.
Compound 13: 2-([1,4]dioxanylmethoxy)(1H-indol—2-yl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin
one.
Compound 12 Compound 13
Compound 12 (57 mg, 0.11 mmol) was dissolved in a mixture of DCM/TFA (1/ 1, 2 mL) and the
reaction was stirred at RT for 6h. The e was evaporated to dryness to recover compound 13 as a TFA
salt.
(1H DMSO-da) 8 ppm 8.11 (1 H, d), 7.95 - 7.86 (2 H, m), 7.57 (1 H, d), 7.43 (1 H, d), 7.15 (1 H, t), 7.10 (1 H,
d), 6.71 (1 H, s), 4.31 - 4.25 (2 H, m), 4.09 (2 H, t), 3.92 - 3.84 (1 H, m), 3.79 (2 H, td), 3.71 - 3.57 (2 H, m),
3.55 - 3.46 (1 H, m), 3.40 (1 H, dd), 3.08 (2 H, t)
MW (calcd): 429.5 MW (obsd): 430.5 (M+1)
Compound 14: 2-([1,4]dioxanylmethoxy)-9 -(6-methoxy—pyridin-3 -yl)-6,7 -dihydro-pyrimido [6,1 -
a]isoquinolinone.
This compound is prepared via general method E using intermediate 11 and 2-methoxy
pyridineboronic acid.
Compound 15: 2-([1,4]di0xanylmeth0xy)(6-triflu0r0methyl—pyridinyl)-6,7-dihydr0-pyrimid0[6,1-
a]is0quinolin0ne.
This compound is prepared Via general method E using ediate 11 and 2-(triflu0r0methyl)
pyridine-S-boronic acid.
Compound 16: 2 -( [1 ,4] dioxan-Z-ylmeth0xy)-9 -(3 -methyl-3H-imidazol—4-ylethynyl)-6,7-dihydr0 -
pyrimido [6,1 -a]is0quinolin0ne.
Synthesis fiJlly described above.
Compound 17: 9-(5-tert-butyl-[1,2,4]0xadiazolylmeth0xy)—2-([1,4]di0xanylmeth0xy)-6,7-dihydr0-
do [6,1 -a]is0quinolin0ne.
] This compound is ed Via general method F using ediate 8 and 5-(tert-butyl)
(chloromethyl)-1 ,2,4-0xadiazole.
Compound 18: 5-[2-([1,4]dioxan-Z-ylmethoxy)0x0-6,7-dihydr0-4H-pyrimid0[6,1-a]is0quinolinyl]-
pyridine-Z-carboxylic acid methylamide.
This compound is prepared Via general method E using intermediate 11 and 2-(N—
methylaminocarbonyl) pyridine-S-boronic acid pinacol ester.
Compound 19: 2-([1 ,4]di0xanylmeth0xy)pentynyl-6,7-dihydr0-pyrimid0[6,1-a]is0quinolin0ne.
This compound is prepared Via general method G using intermediate 11 and pent-l-yne.
Compound 20: 2-([1,4]di0xanylmeth0xy)(2-pyridinyl-ethyl)-6,7-dihydr0-pyrimid0[6,1-
a]is0quinolin0ne.
o/fi o/fi o/fi
3° 3° 3°
0 o o
N / N
oél‘N | 02‘
Intermediate 11
2 5 Intermediate 22 Compound 20
Step I: 2-([I,4]dt0xanylmeth0xy)((E)pyridtnyl—vinyl)-6,7-dihydr0-pyrtmtd0[6,I-ajisoqutnolt'n
one (intermediate 22).
A round bottom flask was charged with ediate 11 (50 mg, 0.11 mol, 1 eq.), 2-Vinylpyridine
(0.014 mL, 0.13 mmol, 1.2 eq.), (DPPF)PdC12.DCM (4.4 mg, 0.0054 mmol, 0.05 eq.) and TEA (0.03
mL, 0.22 mmol, 2 eq.) under N2 then the flask was degassed. DMF (2 mL) was then added and the reaction
was stirred at 100 °C for 16 h. The reaction was cooled to RT and evaporated to dryness, the e was then
d by flash chromatography on silica gel, eluting from 0 to 3% MeOH/DCM affording intermediate 22
2-([1 ,4]dioxanylmethoxy)((E)pyridinyl-vinyl)-6,7-dihydro-pyrimido[6, 1 quinolinone.
(1H, CDC13) 8 ppm 8.66 - 8.59 (1 H, m), 7.74 - 7.53 (4 H, m), 7.46 (1 H, s), 7.39 (1 H, d), 7.30 - 7.15 (2 H,
m), 6.37 (1 H, s), 4.48 — 3.93 (1 H, m), 3.89
- 4.34 (2 H, m), 4.21 (2 H, t), 4.02 - 3.59 (5 H, m), 3.53 - 3.42 (1
H, m), 3.03 (2 H, m)
MW (calcd): 417.5; MW (obsd): 418.4 (M+1)
Step 2: 2-([I,4]dioxanylmethoxy)-9—(2-pyrtdinyZ-ethyD-6,7—dthydro-pyrtmido[6,I-ajt'soqut'noltn-4—one
und 20).
A round bottom flask was charged with intermediate 22 (45 mg, 0.11 mol, 1 eq.), PtOZ (6 mg,
0.025 mmol, 0.23 eq.) and THF (2 mL) was added. The system was purged with N2 before being filled with
H2 then the reaction was stirred for 16 h at RT. The reaction mixture was filtered through a SPE guanidine
cartridge and the solvent was evaporated to dryness. The crude product was purified by flash chromatography
on silica gel, eluting from 1 to 10% CM to give compound 20.
(H, CDC13) 5 ppm 8.58 (1 H, dd), 7.66 - 7.56 (2 H, m), 7.22 (1 H, dd), 7.19 - 7.09 (3 H, m), 6.36 (1 H, s),
4.50 — 3.95 (1 H, m), 3.91
- 4.36 (2 H, m), 4.25 - 4.17 (2 H, m), 4.04 - 3.62 (5 H, m), 3.50 (1 H, dd), 3.14 (4
H, s), 2.98 (2 H, t)
MW (calcd): 419.5; MW : 420.5 (M+1)
Compound 21: 2-([1,4]dioxanylmethoxy)(2-pyrazinyl-ethyl)-6,7-dihydro-pyrimido[6,1-
a]isoquinolinone.
O O
50 50
O O
N ’ N ’
0%N I 0%N I
| j/
Intermediate 11 Intermediate 23 Compound 21
Step I .' 2-([I,4]dioxanylmetnoxy)((E)pyraztnyl—vinyl)-6, 7—dihydro-pyrtmtdo[6,1-a]tsoquinoltn
one (intermediate 23).
A round bottom flask was charged with intermediate 11 (50 mg, 0.11 mol, 1 eq.), 2-vinyl-
pyridine (0.014 mL, 0.13 mmol, 1.2 eq.), (DPPF)PdClz.DCM (4.4 mg, 0.0054 mmol, 0.05 eq.) and TEA (0.03
mL, 0.22 mol, 2 eq.) under N2 then the flask was degassed. DMF (2 mL) was then added and the reaction
2012/076275
was stirred at 100 °C for 16 h. The reaction was cooled to RT and evaporated to dryness, the residue was then
purified by flash chromatography on silica gel, eluting from 0 to 4% MeOH/DCM affording intermediate 23
2 -( [1 ,4 ]dioxanylmethoxy)-9 -((E)pyrazinyl-vinyl)-6 ,7-dihydro-pyrimido [6 ,1 -a]isoquinolinone.
(1H, CDC13) 8 ppm 8.69 (1 H, m), 8.63 - 8.58 (1 H, m), 8.49 (1 H, m), 7.84 - 7.71 (2 H, m), 7.63 (1 H, d),
7.53 (1 H, s), 7.31 (1 H, s), 6.42 (1 H, s), 4.52 - 4.39 (2 H, m), 4.30 - 4.22 (2 H, m), 4.02 (1 H, dd), 3.93 -
3.63 (5 H, m), 3.52 (1 H, dd), 3.08 (2 H, m)
MW (calcd): 418.5; MW (obsd): 419.4 (M+1)
Step 2: 2-([I,4]di0xanylmelh0xy)-9—(2-pyrazinyZ-elhyD-6,7—dihydr0-pyrimid0[6,I-ajisoquinoll'n0ne
(Compound 21).
] A round bottom flask was charged with intermediate 23 (38 mg, 0.09 mol, 1 eq.), PtOZ (5 mg,
0.021 mmol, 0.23 eq.) and THF (2 mL) was added. The system was purged with N2 before being filled with
H2 then the reaction was stirred for 16 h at RT. The reaction mixture was filtered through a SPE guanidine
cartridge and the solvent was evaporated to dryness. The crude product was purified by flash chromatography
on silica gel, g from 1 to 10% MeOH/DCM to give nd 21.
(H, CDC13) 8 ppm 8.55 (1 H, dd), 8.44 (2 H, dd), 7.63 (1 H, d), 7.22 (1 H, dd), 7.15 (1 H, s), 6.36 (1 H, s),
4.36 - 4.53 (2 H, m), 4.17 - 4.26 (2 H, m), 3.95 - 4.07 (1 H, m), 3.61 - 3.93 (5 H, m), 3.51 (1 H, dd), 3.17 (4
H, s), 2.99 (2 H, t)
MW (calcd): 420.5; MW (obsd): 421.5 (M+1)
Compound 22: 4]dioxanylmethoxy)(1H-indolyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin
one.
This compound is prepared via general method E intermediate 11 and using 5-indolylboronic acid.
Compound 23: 2-([1,4]dioxanylmethoxy)(2-methoxy-phenyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-
4-one.
This compound is prepared via general method E using intermediate 11 and 2-
yphenylboronic acid.
Compound 24: 2-([1,4]dioxanylmethoxy)-9 -(5 -methoxy-pyridin-3 -yl)-6,7 -dihydro-pyrimido [6,1 -
a]isoquinolinone.
This nd is prepared via general method E using intermediate 11 and 3-methoxy
pyridineboronic acid pinacol ester.
Compound 25: 2-([1,4]di0xanylmeth0xy)(1H-indazol—S-yl)-6,7-dihydr0-pyrimid0[6,1-a]is0quinolin
one.
This compound is prepared Via general method E using intermediate 11 and 1H-indazole
boronic acid.
Compound 26: 2-([1 ,4]di0xanylmeth0xy)-9 -(4-meth0xy-phenyl)-6,7 -dihydr0-pyrimid0 [6,1 -a]is0quinolin-
4-one.
This compound is prepared Via general method E using intermediate 11 and 4-
methoxyphenylboronic acid.
Compound 27: [1,4]dioxanylmeth0xy)0x0-6,7-dihydr0-4H-pyrimid0[6,1-a]is0quinolinyl]-
benzamide.
This compound is prepared Via l method E using intermediate 11 and 3-
arbonyphenylboronic acid.
Compound 28: 5-[2-([1,4]di0xanylmeth0xy)0x0-6,7-dihydr0-4H-pyrimid0[6,1-a]is0quinolinyl]
fluoro-benzamide.
This compound is ed Via general method E using intermediate 11 and 3-(amin0carb0nyl)
fluorobenzeneboronic acid.
Compound 29: N— {3-[2-([1,4]dioxanylmeth0xy)0x0-6,7-dihydr0-4H-pyrimid0[6,1-a]is0quinolin-9 -yl]-
phenyl} -acetamide.
This compound is prepared Via general method E intermediate 11 and using 3-
acetamidophenylboronic acid.
Compound 30: 9-cyclopr0pylethynyl([1,4]dioxan-Z-ylmethoxy)-6,7 -dihydr0-pyrimid0 [6,1 -a]isoquinolin-
4-one.
] This compound is ed Via general method G intermediate 11 and using ethynyl-
cyclopropane.
Compound 3 1: 2-( [1 ,4 ]di0xanylmeth0xy)-9 -(1-hydr0xy—cyclopentylethynyl)-6 ,7 -dihydr0-pyrimid0 [6 ,1 -
a]is0quinolin0ne.
This compound is ed Via general method G intermediate 11 and using 1-ethynyl-
cyclopentanol.
Compound 32: 2-([1,4]dioxanylmethoxy)pyrimidinyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin
one.
This compound is prepared Via general method E ediate 11 and using 5-pyrimidinylboronic
acid.
Compound 33: 9-cyclohexenyl([1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin
one.
This compound is prepared Via general method E using intermediate 11 and cyclohexene-l-
boronic acid pinacol ester.
Compound 34: 4]dioxanylmethoxy)-9 -(1-methyl-1H-indol-5 -yl)-6,7 -dihydro-pyrimido[6,1-
a]isoquinolinone.
This compound is prepared Via general method E using intermediate 11 and 1-methylindole
boronic acid pinacol ester.
Compound 35: 2-([1,4]dioxanylmethoxy)-9 -(6-methyl-pyridin-3 -yl)-6,7 -dihydro-pyrimido [6,1 -
a]isoquinolinone.
This nd is prepared Via general method E using intermediate 11 and 6-methylpyridin
ylboronic acid.
Compound 36: 2-([1,4]dioxanylmethoxy)pyridinylethynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-
4-one.
] This compound is prepared Via general method G using intermediate 11 and 2-ethynyl-pyridine.
Compound 37: 2-([1,4]dioxanylmethoxy)(3 -methoxy-prop -1 -ynyl)-6 ,7 -dihydro-pyrimido [6 ,1 -
a]isoquinolinone.
This compound is prepared Via general method G using intermediate 11 and 3-methoxy-propyne.
nd 38: 5-[2-([1,4]dioxanylmethoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolinyl]-
pentynenitrile.
This compound is prepared Via general method G using intermediate 11 and -ynenitrile.
Compound 39: 2-([1,4]dioxanylmethoxy)(3 -hydroxy—prop-1 -ynyl)-6,7 -dihydro-pyrimido [6,1 -
a]isoquinolinone.
] This compound is prepared Via general method G using intermediate 11 and propynol.
Compound 40: 2-([1,4]dioxanylmethoxy)(4-methoxy-phenylethynyl)-6,7-dihydro-pyrimido[6,1-
a]isoquinolinone.
This compound is prepared Via general method G using intermediate 11 and 1-ethynyl
methoxy-benzene.
Compound 41: 2-([1,4]dioxanylmethoxy)pyridinylethynyl-6,7-dihydro-pyrimido[6,1-a]isoquinolin-
4-one.
This compound is prepared Via general method G using intermediate 11 and 3-ethynyl-pyridine
Compound 42: 4-[2-([1,4]dioxanylmethoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolinyl]-N—
methyl-benzamide.
This compound is prepared Via general method E using intermediate 11 and 4-(N—
methylaminocarbonyl)phenylbor0nic acid.
nd 43: 2-([1,4]dioxanylmethoxy)(3-methoxy-phenyl)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-
4-one.
This compound is prepared Via general method E using intermediate 11 and 3-
methoxyphenylboronic acid.
Compound 44: hloro-phenyl)([1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin
one.
This compound is prepared Via general method E using intermediate 11 and 2-
chlorophenylboronic acid.
Compound 45: 2-([1,4]dioxanylmethoxy)-9 -(4-hydroxy-but-1 -ynyl)-6 ,7 -dihydro-pyrimido [6 ,1 -
a]isoquinolinone.
This compound is prepared Via general method G using ediate 11 and butynol.
Compound 46: 9-(1,5-dimethyl-1H-pyrazolylmethoxy)—2-([1,4]dioxanylmethoxy)-6,7-dihydro-
pyrimido [6,1 -a]isoquinolinone.
This compound is ed Via general method F using intermediate 8 and romethyl-1,5-
dimethyl- 1 H-pyrazole.
C0mpound 47: 2 -( [1 ,4] dioxanylmethoxy)-9 -(1 -methyl-1H-pyrazol-3 -ylmethoxy)-6,7-dihydro -
pyrimido [6,1 -a]isoquinolinone.
This compound is prepared via general method F using intermediate 8 and 3-chloromethyl
methyl-1 H-pyrazole.
Compound 48: 2-([1,4]dioxanylmethoxy)(3-methyl-[1,2,4]oxadiazol-S-ylmethoxy)-6,7-dihydro-
pyrimido [6,1 -a]isoquinolinone.
This compound is prepared via l method F using intermediate 8 and 5-chloromethyl
methyl-[1,2,4]oxadiazole.
Compound 49: 2-([1,4]dioxanylmethoxy)—9-(4-morpholinyl-phenyl)-6,7 ro-pyrimido [6,1 -
uinolinone.
This compound is prepared via general method E using intermediate 11 and 4-
morpholinophenylboronic acid, with CsF as base and DMF as solvent.
Compound 50: 3-[2-([1,4]dioxanylmethoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolinyl]
benzamide.
] This compound is prepared via general method E using intermediate 11 and 5-carbamoyl
fluorobenzeneboronic acid, with CsF as base and DMF as solvent.
Compound 51: 3-[2-([1,4]dioxanylmethoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolinyl]
fluoro-benzamide.
This compound is prepared via general method E using intermediate 11 and 3-(aminocarbonyl)
fluorobenzeneboronic acid, with CsF as base and DMF as solvent.
nd 52: 9 -(3 ,3 -Dimethyl-butynyl)([1,4]dioxanylmethoxy)-6 ,7 -dihydro-pyrimido [6 ,1 -
a]isoquinolinone.
This compound is prepared via l method G using ediate 11 and 3,3-dimethyl-but
yne.
Compound 53: 2-([1,4]dioxanylmethoxy)-9 -pyridinylethynyl-6,7 -dihydro-pyrimido [6,1 -a]isoquinolin-
4-one.
This compound is prepared via general method G using intermediate 11 and 4-ethynyl-pyridine.
nd 54: 2-([1,4]di0xanylmeth0xy)(3 -methyl-is0xazol-5 -ylmeth0xy)-6,7 -dihydr0-pyrimid0 [6,1 -
a]is0quin01in0ne.
This compound is prepared Via general method F using ediate 8 and 5-chlor0methyl
methyl-isoxazole.
Compound 55: 2-([1,4]di0xanylmeth0xy)—9-(3 xy-3 -methyl-but-1 -ynyl)-6 ,7 -dihydr0-pyrimid0 [6 ,1 -
a]is0quin01in0ne.
This compound is prepared Via general method G using intermediate 11 and 2-methyl—butyn
Compound 56: 2-([1 ,4]di0xanylmeth0xy)(2-meth0xy—pyridin-3 ,7 -dihydr0-pyrimid0[6,1 -
a]is0quin01in0ne.
This compound is prepared Via l method E using intermediate 11 and 2-meth0xy
pyridinyl boronic acid.
Compound 57 : 2-([1,4]di0xanylmeth0xy)-6,7-dihydr0-pyrimid0[6,1-a]is0quinolin0ne.
This compound is prepared Via general method E using intermediate 11 and ium
(cyanomethyl) trifluoroborate.
Compound 58: 9 -(3 ,6-dihydr0-2H-pyranyl)—2-([1,4]dioxan-Z-ylmethoxy)-6,7 -dihydr0-pyrimid0 [6,1 -
a]is0quin01in0ne.
This compound is prepared Via general method E using intermediate 11 and 3,6-dihydro-2H-
pyranb0r0nic acid pinacol ester.
nd 59: 5-[2-([1,4]dioxan-Z-ylmethoxy)0x0-6,7-dihydr0-4H-pyrimid0[6,1-a]is0quinolinyl]-
pyridine-Z-carb onitrile.
This compound is prepared Via general method E using intermediate 11 and 2-cyan0pyridine
boronic acid pinacol ester.
Compound 60: 4]Di0xanylmeth0xy)(6-is0pr0p0xy—pyridinyl)-6,7-dihydr0-pyrimid0[6,1-
a]is0quin01in0ne.
This compound is prepared Via general method E using intermediate 11 and 6-
isopropoxypyridineb0r0nicacid pinacol ester.
Compound 61: 2-([1,4]di0xanylmeth0xy)-9 -(6-eth0xy—pyridin-3 -yl)-6,7 -dihydr0-pyrimid0 [6,1 -
a]is0quin01in0ne.
This compound is prepared Via general method E using intermediate 11 and 6-eth0xypyridine
boronic acid.
nd 62: 2-([1,4]di0xanylmeth0xy)(6-m0rpholinyl-pyridinyl)-6,7-dihydr0-pyrimid0[6,1-
a]is0quin01in0ne.
This compound is prepared Via general method E using intermediate 11 and 4,4,5,5-
tetramethyl-1 ,3 ,2-di0xab0rolanyl)pyridinyl]m0rpholine.
Compound 63: 9-(2,3 -dimeth0xy—phenyl)—2-([1,4]dioxan-Z-ylmethoxy)-6,7 -dihydr0-pyrimid0 [6,1 -
a]is0quin01in0ne.
This nd is prepared Via general method E using intermediate 11 and 2,3-
dimethoxyphenylboronic acid.
Compound 64: 9-(3-chlor0meth0xy—pyridinyl)([1,4]di0xanylmeth0xy)-6,7-dihydr0-
pyrimido [6,1 -a]is0quinolin0ne.
This nd is prepared Via general method E using intermediate 11 and r0
methoxypyridineb0r0nic acid.
Compound 65: 4]di0xanylmeth0xy)-9 -(2-methyl-pyridinyl)-6,7 r0-pyrimid0 [6,1 -
a]is0quin01in0ne.
This compound is prepared Via general method E using intermediate 11 and 2-methylpyridine
boronic acid pinacol ester.
nd 66: 3-[2-([1,4]dioxan-Z-ylmethoxy)0x0-6,7-dihydr0-4H-pyrimid0[6,1-a]is0quinolinyl]-
isonicotinonitrile.
This compound is prepared Via general method E using intermediate 11 and 4-cyan0pyridine
boronic acid pinacol ester.
Compound 67 : 9-(2,5 -dimeth0xy—phenyl)—2-([1,4]dioxan-Z-ylmethoxy)-6,7 -dihydr0-pyrimid0 [6,1 -
a]is0quin01in0ne.
This compound is prepared Via general method E using intermediate 11 and 2,5-
dimethoxyphenylboronic acid.
Compound 68: 2-([1,4]dioxanylmethoxy)(3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl)-6,7-dihydropyrimido
[6,1 -a]isoquinolinone.
This compound is ed Via general method E using intermediate 11 and 1-[5-(4,4,5,5-
tetramethyl-1 ,3 ,2-dioxaborolanyl)pyridinyl]piperidine.
Compound 69: 2-([1,4]dioxanylmethoxy)-9 -(2-ethoxy—pyridin-3 -yl)-6,7 -dihydro-pyrimido [6,1 -
uinolinone.
] This compound is prepared Via general method E using intermediate 11 and 2-ethoxypyridine
boronic acid.
Compound 70: 9-(2 ,6 -dimethoxy—pyridinyl)([ 1 ,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1 -
a]isoquinolinone.
] This compound is prepared Via general method E using intermediate 11 and 2,6-dimethoxy
pyridineboronic acid.
Compound 71: 4-[2-([1,4]dioxanylmethoxy)oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolinyl]-
nicotinonitrile.
This compound is ed Via l method E using intermediate 11 and 3-cyanopyridine
boronic acid, pinacol ester.
Compound 72: 9-tert-butoxymethyl([1,4]dioxan-Z-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin
one.
This compound is prepared Via general method E using intermediate 11 and potassium tert-
butoxymethyltrifluoroborate.
Compound 73: 2-([1,4]dioxanylmethoxy)(2-pyrrolidinyl-pyridinyl)-6,7-dihydro-pyrimido[6,1-
a]isoquinolinone.
This compound is prepared Via general method E using intermediate 11 and rolidinyl)
(4,4,5 ,5 -tetramethyl- 1 ,3 ,2 -dioxab orolan-2 ridine.
Compound 74: 2-([1,4]dioxanylmethoxy)(6-pyrrolidinyl-pyridinyl)-6,7-dihydro-pyrimido[6,1-
a]isoquinolinone.
This compound is prepared Via general method E using intermediate 11 and 2-(1-pyrrolidinyl)
(4,4,5 ,5 -tetramethyl- 1 ,3 ,2 -dioxab orolan-2 -yl)pyridine.
Compound 75: 2-([1,4]di0xanylmeth0xy)(5-phenyl-0xazolylmeth0xy)-6,7-dihydr0-pyrimid0[6,1-
a]is0quin01in0ne.
This compound is prepared Via general method F using intermediate 8 and 2-chlor0methyl
phenyl-oxazole.
Compound 76: 9-(5-tert-butyl-0xaz01—2-ylmeth0xy)—2-([1,4]dioxan-Z-ylmethoxy)-6,7-dihydr0-pyrimid0[6,1-
a]is0quin01in0ne.
This compound is prepared Via l method F using intermediate 8 and 5-tert-butyl
chloromethyl-oxazole.
Compound 77: 9-(5-cyclopr0pyl-[1,2,4]0xadiazolylmeth0xy)—2-([1 ,4]di0xanylmeth0xy)-6,7-dihydr0-
pyrimido [6,1 quinolin0ne.
This nd is prepared Via general method F using intermediate 8 and 3-chlor0methyl
cyclopropyl— [ 1 ,2,4] oxadiazole.
Compound 78: 2-([1,4]di0xanylmeth0xy)-9 -(5 -ethyl-[1,2,4]0xadiazol-3 h0xy)-6,7-dihydr0-
pyrimido [6,1 -a]is0quinolin0ne.
This compound is prepared Via general method F using intermediate 8 and 3-chlor0methyl
ethyl-[1,2,4]0xadiazole.
Compound 79: 2-([1,4]di0xanylmeth0xy)-9 -(5 -methyl-[1,2,4]0xadiazol-3 -ylmeth0xy)-6,7-dihydr0-
pyrimido [6,1 -a]is0quinolin0ne.
This compound is prepared Via general method F using intermediate 8 and 3-chlor0methyl
methyl-[1,2,4]0xadiazole.
Compound 80: 2-([1 ,4]di0xanylmeth0xy)-9 -(5 0pyl—[1,2,4]0xadiazol-3 h0xy)-6,7-dihydr0-
pyrimido [6,1 -a]is0quinolin0ne.
This compound is prepared Via general method F using intermediate 8 and 3-chlor0methyl
isopropyl- [ 1 ,2,4] zole.
Compound 81: 9-cyclopentylethynyl([1,4]dioxan-Z-ylmethoxy)-6,7 -dihydr0-pyrimid0 [6,1 -a]is0quinolin-
4-0ne.
This compound is ed Via general method G using intermediate 11 and ethynyl-
cyclopentane.
Compound 82: 9 -cyclohexylethynyl([1,4]dioxan-Z-ylmethoxy)-6,7 -dihydro-pyrimid0 [6,1 -a]isoquinolin-
4-one.
This compound is prepared via general method G using intermediate 11 and ethynyl-cyclohexane.
Compound 83: 2-( [1 ,4 ]di0xanylmeth0xy)-9 -(3 -methyl-but-1 -ynyl) -6 ,7 -dihydr0-pyrimid0 [6 ,1 -
a]isoquinolin0ne.
] This compound is prepared via general method G using intermediate 11 and 3-methyl-butyne.
Compound 84: 2-([1 ,4]di0xanylmeth0xy)hex-1 -ynyl-6,7-dihydr0-pyrimid0[6,1-a]is0quinolin0ne.
[00344] This compound is prepared via general method G using intermediate 11 and hex-1 -yne.
Compound 85: 9- [3 -(benzyl-methyl-amin0)-pr0pynyl]([1 ,4]di0xanylmeth0xy)-6,7-dihydr0-
pyrimido [6,1 -a]is0quinolin0ne.
This compound is prepared via general method G using intermediate 11 and benzyl—methyl—prop-
2-ynyl-amine.
Compound 86: 2-([1,4]di0xanylmeth0xy)(3-hydr0xy-5 -methyl-hex-1 -ynyl)-6,7 r0-pyrimid0[6,1 -
a]isoquinolin0ne.
] This compound is prepared via general method G using intermediate 11 and 5-methyl-hexyn
01, with lPerH as base and THF as t.
Compound 87 : 2-([1,4]dioxanylmeth0xy)-9 -(3 -hydr0xy-but-1 -ynyl)-6,7 -dihydr0-pyrimid0 [6,1 -
a]isoquinolin0ne.
This compound is prepared via general method G using ediate 11 and ynol, with
iPrZNH as base and THF as solvent.
Compound 88: 9-cyclopr0pyl—2-([1,4]dioxan-Z-ylmethoxy)-6,7 -dihydro-pyrimid0 [6,1 quinolinone.
This compound is prepared via general method E using intermediate 11 and potassium
cyclopropyltrifluoroborate.
Compound 89: 2-([1 xanylmeth0xy)(3 xy—pent-1 -ynyl)-6,7 -dihydr0-pyrimid0 [6,1 -
a]isoquinolin0ne.
This compound is prepared via general method G using intermediate 11 and pentynol with
iPrZNH as base and THF as solvent.
Compound 90: 2-([1,4]Di0xanylmeth0xy)—9-(3 -hydr0xy—4-methyl-pent-1 -ynyl)-6,7-dihydr0-
pyrimido [6,1 -a]is0quinolin0ne.
This compound is prepared via general method G using intermediate 11 and 4-methyl-pentyn-
3-01 with iPrZNH as base and THF as t.
Compound 91: 2-([1,4]dioxan-Z-ylmethoxy)(3 -ethylhydr0xy—pentynyl)-6,7-dihydr0-
pyrimido [6,1 -a]is0quinolin0ne.
This compound is prepared via general method G using intermediate 11 and 3-ethyl-pentyn
01 with iPrZNH as base and THF as t.
Compound 92: 2-([1,4]dioxan-Z-ylmethoxy)(3-hydr0xy—3-phenyl-butynyl)-6,7-dihydr0-pyrimid0[6,1-
a]is0quinolin0ne.
This compound is prepared via l method G using intermediate 11 and 2-phenyl—butyn
01 with Cs2C03 as base and MeCN as solvent under reflux.
Compound 93: 9-(3 -benzylamin0-pr0pynyl)([1,4]di0xanylmeth0xy)-6,7 -dihydr0-pyrimid0 [6,1 -
uinolin0ne.
This nd is prepared via general method G using intermediate 11 and benzyl-prop-Z-ynylamine
with Cs2C03 as base and MeCN as solvent under reflux.
Compound 94: 2-([1,4]di0xanylmeth0xy)[(furan-Z-ylmethyl)-amin0]-6,7-dihydr0-pyrimid0[6,1-
a]is0quinolin0ne.
ON ON
° 5°
0 O
O N O N
OTf Nmm
Intermediate 11 Compound 94
A suspension of intermediate 11 (200 mg, 0.433 mol, 1 eq.), fiJran-Z-ylmethanamine (0.038 mL,
0.433 mol, 1 eq.) and Cs2C03 (0.17g, 0.519 mmol, 1.2 eq.) in toluene (4 mL) was degassed with Ar for 30
min before BINAP (+/—) (16 mg, 0.026 mmol, 0.06 eq.) and )2 (3.88 mg, 0.017 mmol, 0.04 eq.) were
added. The reaction was heated to 65 °C for 16 h. The reaction was cooled to RT, BINAP (+/—) (16 mg, 0.026
mmol, 0.06 eq.) and Pd(OAc)2 (3.88 mg, 0.017 mmol, 0.04 eq.) were added and the reaction was degassed.
The on was heated to 80 °C for 1 extra day. The reaction was cooled to RT, BINAP (+/—) (16 mg, 0.026
mmol, 0.06 eq.) and Pd(OAc)2 (3.88 mg, 0.017 mmol, 0.04 eq.) were added and the on was degassed.
The reaction was heated to 80 °C for 1 extra day. The reaction was cooled to RT and diluted with DCM and
washed with 0.5N aqueous KHSO4. The aqueous layer was extracted with DCM, the combined organic layers
were dried over Na2S04 and evaporated to dryness. The crude product was purified by preparative HPLC-MS
[H20 (9892): MeCN (29 98) / 0.1%HC02H] to give compound 94.
(H, CDC13) 5 ppm 7.57 - 7.48 (1 H, d), 7.38 (1 H, s), 6.68 - 6.55 (1 H, d), 6.49 (1 H, s), 6.35 (1 H, s), 6.28 (1
H, s), 6.20 (1 H, s), 4.60 - 4.50 (1 H, m), 4.38 - 4.30 (4 H, m), 4.22 - 4.15 (2 H, m), 4.03 - 3.93 (1 H, m), 3.95
- 3.60 (5 H, m), 3.55 -3.40 (1 H, t), 2.98 - 2.85 (2 H, m)
MW (calcd): 409.4; MW (obsd): 410.2 (M+1)
Compound 95: 2-([1,4]dioxanylmethoxy)-9 -(1-ethyl-1H-pyrazolyl)-6,7 -dihydro-pyrimido [6,1 -
a]isoquinolinone.
This compound is prepared via general method E using intermediate 11 and 1-ethyl-1H-pyrazole-
4-boronic acid, pinacol ester.
Compound 96: 4]dioxanylmethoxy)-9 -[1-(3 -methyl-butyl)-1H-pyrazolyl]-6,7-dihydropyrimido
[6,1 -a]isoquinolinone.
] This compound is prepared via l method E using intermediate 11 and 1-(3-methylbutyl)-
1H-pyrazoleboronic acid, pinacol ester.
Compound 97: 2-([1,4]dioxanylmethoxy)-9 -(5 -methyl-furanyl)-6,7 -dihydro-pyrimido [6,1 -
a]isoquinolinone.
This compound is prepared via l method E using intermediate 11 and 2-methylfurane
boronic acid pinacol ester.
nd 98: 2-([1,4]dioxanylmethoxy)-9 -(3 -hydroxy-hex-1 -ynyl)-6,7 -dihydro-pyrimido [6,1 -
a]isoquinolinone.
This compound is prepared via general method G using intermediate 11 and hexynol,
Cs2C03 as base and MeCN as solvent under reflux.
Compound 99: 9-(3 ,5 -dimethyl-1H-pyrazolyl)—2-([1,4]dioxanylmethoxy)-6,7 -dihydro-pyrimido [6,1 -
uinolinone.
This compound is prepared via general method E using intermediate 11 and 3,5 -dimethylpyrazole-
4-boronic acid pinacol ester.
Compound 100: 2-([1,4]di0xanylmeth0xy)(1H-pyrazol—4-yl)-6,7-dihydr0-pyrimid0[6,1-a]is0quinolin-
4-one.
This compound is ed Via general method E using intermediate 11 and pyrazoleb0r0nic
acid l ester.
Compound 101: 2-([1,4]dioxan-Z-ylmethoxy)(1-pr0pyl-1H-pyrazolyl)-6,7-dihydr0-pyrimid0[6,1-
a]is0quin01in0ne.
] This compound is prepared Via general method E using intermediate 11 and l-propyl-lH-
pyrazoleboronic acid, pinacol ester.
Compound 102: 2-[2-((R)[1,4]di0xanylmeth0xy)0x0-6,7-dihydr0-4H-pyrimid0[6,1-a]is0quinolin
yl]-benz0nitrile.
This compound is prepared Via general method E using intermediate 10 and 2-
cyanophenylboronic acid l ester.
Compound 103: 2-[2-((S)[1,4]di0xanylmeth0xy)0x0-6,7-dihydr0-4H-pyrimid0[6,1-a]is0quinolin
yl]-benz0nitrile.
This compound is prepared Via general method E using intermediate 9 and 2-cyan0phenylb0r0nic
acid pinacol ester.
Compound 104: 9-(5 propyl-[1,2,4]0xadiazol—3 hoxy)—2-((R)[1,4]dioxan-Z-ylmethoxy)-6,7 -
dihydro-pyrimid0[6,1 -a]is0quinolin0ne.
This compound is prepared Via general method F using intermediate 7 and 3-chlor0methyl
cyclopropyl— [ 1 ,2,4] oxadiazole.
Compound 105: 2-([1,4]dioxan-Z-ylmethoxy)—9-ethynyl-6,7-dihydr0-pyrimid0[6,1-a]is0quinolin0ne.
o/fio o 0/}
0 O 0
Step 1 Step 2
N / ———> N / ———> N /
0%N I I I
O N O N
OTf § %
SiMe3
Intermediate 11 Intermediate 24 Compound 105
Step I .' 2-([I,4]dt0xanylmeth0xy)pr0p-I 6, 7—dihydr0-pyrtmtdo[6, I -a]t's0quinoltn0ne
(Intermediate 24).
Intermediate 24 2-([1,4]dioxanylmethoxy)propynyl-6,7-dihydro-pyrimido[6,1-
a]isoquinolinone is synthesised via general method E with intermediate 11 and ethynyl-trimethyl-silane.
(1H, CDC13) 5 ppm 7.66 - 7.61 (1 H, m), 7.47 - 7.43 (1 H, m), 7.42 - 7.38 (1 H, m), 6.37 (1 H, s), 4.50 - 4.36
(2 H, m), 4.23 — 3.93 (1 H, m), 3.90 — 2.97 (1
- 4.16 (2 H, m), 4.04 - 3.60 (4 H, m), 3.53 - 3.44 (1 H, m), 3.02
H, m), 0.27 (7 H, s)
MW ): 410.5; MW (obsd): 411.4 (M+1)
Step 2: 2-([I ,4]dt0xanylmeth0xy)ethynyl—6, dr0-pyrtmtdo[6,1 -a]tsoqutnolin-4—0ne (Compound
I 05).
TBAF (4.06 mL, 4.06 mmol, 1.2 eq.) was added dropwise to a solution of intermediate 24 (1.39 g,
3.39 mmol, 1 eq.) in THF (40 mL) at 0 °C and the on was stirred for 1 h at 0 °C. The reaction was then
evaporated to dryness, and the residue was re-dissolved in HCl 1N. The aqueous phase was extracted with
DCM, the combined organic layers were dried over MgSO4 and the solvent evaporated under vacuum. The
crude product was ed by flash chromatography on silica gel, eluting from 0 to 5% MeOH/DCM to
furnish compound 105.
(H, CDC13) 6 ppm 7.65 (1 H, s), 7.51 - 7.46 (1 H, m), 7.45 - 7.41 (1 H, m), 6.37 (1 H, s), 4.49 - 4.36 (2 H,
m), 4.21 (2 H, s), 4.04 — 3.94 (1 H, m), 3.90 - 3.61 (5 H, m), 3.53 - 3.44 (1 H, m), 3.25 (1 H, s), 3.00 (2 H, s)
MW ): 330.3; MW (obsd): 331
Compound 106: 2-([1 ,4]dioxanylmethoxy)pyrimidinylethynyl-6,7 -dihydro-pyrimido [6,1 -
a]isoquinolinone.
I —>
O N
Compound 105 Compound 106
[00368] Compound 105 (50 mg, 0.15 mol, 1 eq.) was dissolved in DMF (3 mL), 5-bromo-pyrimidine (47
mg, 0.30 mmol, 2 eq.) was added followed by TEA (0.062 mL, 0.44 mmol, 3 eq.), and the mixture was
degassed. Pd(PPh3)3C12 (5 mg, 0.0074 mmol, 0.05 eq.) was added with CuI (6 mg, 0.029 mmol, 0.2 eq.) and
the reaction mixture was heated at 80 °C for 16 h. The volatiles were evaporated to dryness and the crude
product was purified by flash tography on silica gel, eluting from 0 to 5% MeOH/DCM to give
compound 106.
Compound 107 : 2-([1,4]dioxanylmethoxy)(3-phenylamino-propynyl)-6,7-dihydro-pyrimido[6,1-
a]isoquinolinone.
This nd is prepared via general method G using intermediate 11 and phenyl-propynylamine
with iPrZNH as base and THF as solvent.
Compound 108: 2-([1,4]dioxanylmethoxy)-9 -(3 -hydroxy—3 -pyridin-3 -yl-prop-1 -ynyl)-6,7-dihydro-
pyrimido [6,1 -a]isoquinolinone.
This nd is ed via general method G using intermediate 1 1 and 1 -pyridin-3 -yl-prop-
2-yn01.
Compound 109: 9 -cyclopentyloxymethyl—2-([ 1 ,4]dioxanylmethoxy)-6,7 -dihydro-pyrimido [6,1 -
uinolinone.
This compound is prepared via general method E using intermediate 11 and potassium
cyclopentoxymethyltrifluoroborate.
Compound 1 1 0: 2-([1,4]dioxanylmethoxy)—9-(3 -methoxymethyl-pentynyl)-6,7-dihydro-
pyrimido [6 ,1 -a]isoquinolinone.
Synthesis fiJlly described above.
Compound 1 1 1: 9-cyclopropylethynyl—2-((R)-1 -[1,4]dioxan-Z-ylmethoxy)-6,7 -dihydro-pyrimido [6,1 -
uinolinone.
This compound is prepared via general method G using intermediate 10 and ethynyl-
cyclopropane.
Compound 1 12: 2-((S)[1,4]dioxanylmethoxy)(3 -methyl-butynyl)-6,7 -dihydro-pyrimido[6,1-
a]isoquinolinone.
This compound is prepared via general method G using intermediate 9 and 3-methyl-butyne.
Compound 1 13: 2-([1 ,4]Dioxanylmethoxy)-9 -(3 -imidazol-1 -yl-prop-1 -ynyl)-6,7 -dihydro-pyrimido [6,1 -
a]isoquinolinone.
This compound is prepared via general method G using intermediate 11 and 1-propynyl-1H-
imidazole.
Compound 1 14: 9-(2-cyclopropyl-ethyl)((R)-1 -[1,4]dioxanylmethoxy)-6,7 -dihydro-pyrimido [6,1 -
a]isoquinolinone.
O/fi o/fi
3"
O O
I i’ I
O N O N
ediate 10 Compound 114
A round bottom flask was charged with intermediate 10 (2 g, 4.33 mol, 1 eq.), intermediate 20
(1.1 g, 6.5 mmol, 1.5 eq.), K2CO3 (1.8 g, 13 mol, 3 eq.), Pd(OAc)2 (19 mg, 0.087 mmol, 0.02 eq.), RuPhos
(81 mg, 0.173 mmol, 0.04 eq.), toluene (30 mL) and H20 (3 mL). The mixture was degassed with N2 and was
heated at 80 °C for 16 h. The reaction was cooled to RT, ed with brine and extracted with EtOAc. The
organic layer was dried over MgSO4 and evaporated to dryness. The crude product was purified by flash
chromatography on silica gel, eluting from 70 to 90% EtOAc/H to give compound 114.
(H, CDC13) 8 ppm 7.64 - 7.58 (1 H, m), 7.24 - 7.19 (1 H, m), 7.13 (1 H, s), 6.35 (1 H, s), 4.49 - 4.36 (2 H,
m), 4.25 — 3.95 (1 H, m), 3.90 — 2.95 (2 H,
- 4.17 (2 H, m), 4.03 - 3.61 (5 H, m), 3.54 - 3.45 (1 H, m), 3.02
m), 2.81 - 2.72 (2 H, m), 1.59 - 1.49 (2 H, m), 0.77 - 0.64 (1 H, m), 0.49 - 0.42 (2 H, m), 0.10 - 0.02 (2 H, m)
MW (calcd): 382.5; MW (obsd): 383.4 (M+1)
Compound 115: 9-cyclopentyloxymethyl((R)-1 -[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1 -
a]isoquinolinone.
[00377] This nd is prepared via general method E using intermediate 10 and potassium
cyclopentoxymethyltrifluoroborate.
Compound 116: 2-([1,4]dioxanylmethoxy)(3 -hydroxypyridinyl-propyl)-6,7-dihydropyrimido
[6 ,1 -a]isoquinolinone.
[00378] Synthesis fiJlly bed above.
Compound 1 17 : 9 oxy((R)-1 -[1,4]dioxanylmethoxy)-6,7 -dihydro-pyrimido [6,1 -a]isoquinolin
one.
sis fiJlly described above.
2012/076275
Compound 1 18: 9-allyloxy—2-((S)[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin
one.
Synthesis fiJlly described above.
Compound 1 19: 2-((R)[1 ,4]dioxanylmethoxy)(tetrahydro-pyranyloxymethyl)-6,7-dihydro-
pyrimido [6,1 quinolinone.
This compound is prepared via general method E using intermediate 10 and intermediate 14.
Compound 120: 2-([1 ,4]dioxan-Z-ylmethoxy)—9- {3 -[(pyridin-3 -ylmethyl)-amino]-propynyl}-6,7-dihydro-
pyrimido [6,1 -a]isoquinolinone.
] This compound is ed via general method G using intermediate 11 and prop-Z-yn-l-
yl(pyridinylmethyl)amine.
Compound 12 1: 2-((R)[1,4]dioxan-Z-ylmethoxy)—9-pentyl-6,7-dihydro-pyrimido[6,1-a]isoquinolinone.
This Compound is prepared via general method I using compound 111.
Compound 122: 9-cyclopropylethynyl—2-((S)[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1-
a]isoquinolinone.
[00384] Intermediate 9 (13.5 g, 29.20 mmol, 1 eq.) was dissolved in degassed DMF (1000 mL) under an
nitrogen atmosphere, ethynyl cyclopropane (3.5 g, 53.00 mmol, 1.8 eq.) was added followed by Pd(PPh3)3C12
(1.11 g, 1.58 mmol, 0.05 eq.), CuI (1.9 g, 9.98 mmol, 0.34 eq.) and TEA (12.5 mL, 89.7 mmol, 3.1 eq.). The
reaction mixture was stirred 3h at 80 °C and 15 h at room temperature. The reaction was concentrated under
vacuum. The crude product was then purified by ation in hot iPrOH to afford compound 122.
] (1H, CDC13) 5 ppm 7.63 (1 H, d), 7.39 (1 H, dd), 7.31 (1 H, s), 6.36 (1 H, s), 4.50 - 4.39 (2
H, m), 4.20 (2 H, t), 4.02 - 3.98 (1 H, m), 3.89 - 3.66 (5 H, m), 3.49 (1 H, t), 2.96 (2 H, t), 1.59 -
1.48 (1 H, m), 0.98 - 0.81 (4 H, m)
MW (calcd): 378.4; MW (obsd): 379.4
ee = 98.3%
WO 92791
Compound 123: 9 -(2-cyclopropyl-ethyl)((S) [1 ,4]dioxanylmethoxy)—6,7-dihydropyrimido [6,1 -
a]isoquinolinone.
O O
i" —» Na
0 N CAN
Intermediate 9 Compound 123
A round bottom flask was charged with intermediate 9 (2.08 g, 4.51 mol, 1 eq.), intermediate 20
(1.35 g, 7.67 mmol, 1.7 eq.), K2CO3 (1.87 g, 13.53 mol, 3 eq.), Pd(OAc)2 (20 mg, 0.09 mmol, 0.02 eq.),
RuPhos (84 mg, 0.18 mmol, 0.04 eq.), toluene (30 mL) and H20 (3 mL). The mixture was degassed with N2
and was heated at 80 °C for 1.5 days. The reaction was cooled to RT and some more reagents were added,
potassium 2-cyclopropyl-ethyl-trifluoroborate (0.3 eq.), Pd(OAc)2 (0.02 eq.), RuPhos (0.04 eq.), the reaction
was degassed and the reaction was heated at 80 °C for 16h. The reaction was cooled to RT, quenched with
H20 and extracted with EtOAc. The organic layer was dried over MgSO4 and ated to dryness. The
crude product was purified by flash chromatography on silica gel, eluting from 80 to 90% EtOAc/H to
compound 123.
(H, CDC13) 6 ppm 7.64 - 7.58 (1 H, m), 7.24 - 7.19 (1 H, m), 7.13 (1 H, s), 6.35 (1 H, s), 4.49 - 4.36 (2 H,
m), 4.24 — 3.95 (1 H, m), 3.91 — 2.95 (2 H, m), 2.81
- 4.17 (2 H, m), 4.03 - 3.62 (5 H, m), 3.49 (1 H, dd), 3.03
- 2.73 (2 H, m), 1.59 - 1.50 (2 H, m), 0.71 (1 H, s), 0.49 - 0.42 (2 H, m), 0.09 - 0.03 (2 H, m)
MW (calcd): 382.5; MW : 383.4
Compound 124: 2-((S)[1 ,4]dioxanylmethoxy)-9 -(oxetan-3 -yloxymethyl)-6,7 -dihydro-pyrimido [6,1 -
a]isoquinolinone.
[00387] This nd is ed Via general method E using intermediate 9 and intermediate 15.
Compound 125: 2-((S)[1,4]dioxanylmethoxy)(3 l-oxetan-3 -ylmethoxymethyl)-6,7-dihydro-
do [6,1 -a]isoquinolinone.
This compound is prepared Via general method E using intermediate 9 and intermediate 16.
Compound 126: 9-(2,2-dimethyl-butylamino)—2-((S)-1 -[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1 -
a]isoquinolinone.
Synthesis fiJlly described above.
Compound 127 : 2-((S)[1,4]di0xanylmeth0xy)(3-hydr0xymethyl-pentyl)-6,7-dihydr0-
pyrimido [6,1 -a]is0quinolin0ne.
o 0/} 0
$0 0
_ $0
0/ o/ 0/-
SteP 1 Step 2
N , N , N /
DAN | DAN | CAN I
OTf Q
Intermediate 9 Intermediate 25 Compound 127
Step I .' 2-((S)-I -[I ,4]Di0xanylmeth0xy)(3-hydr0xymethyl—pent—I -ynyl)-6, 7—dt'hydr0-pyrt'mtd0[6,1 -
utnolin0ne (Intermediate 25)
Intermediate 25 is prepared Via general method G using intermediate 9, 4-Methyl-pentynol,
tPrZNH as base and THF as solvent.
(1H, CDC13) 5 ppm 7.65 - 7.60 (1 H, d), 7.48 - 7.40 (1 H, m), 7.37 (1 H, s), 6.36 (1 H, s), 4.50 - 4.30 (3 H, m),
4.25 - 4.15 (2 H, m), 4.05 - 3.95 (1 H, m), 3.92 - 3.60 (6 H, m), 3.68 - 3.40 (1 H, m), 3.05 - 2.92 (2 H, m),
2.10 - 1.95 (1 H, m), 1.93 - 1.80 (1 H, m), 1.15 - 1.00 (6 H, m)
MW (calcd): 410.5; MW (obsd): 411.2 (M+1)
Step 2 .' 2-((S)-I -[I , 4]dioxan-Z-ylmethoxy) (3-hydr0xy-4—methyl—pentyl)-6, 7—dthydr0-pyrtmtd0[6, I -
utnolin0ne und 12 7)
[00391] Compound 127 is prepared Via general method I using intermediate 25.
Compound 128: 2-((S)[1,4]di0xanylmeth0xy)(2-ethyl—hexylamin0)-6,7-dihydr0-pyrimid0[6,1-
a]is0quinolin0ne.
This nd is prepared Via general method J using intermediate 13 and 2-ethyl-hexanal.
Compound 129: 2-((S)—1-[1,4]di0xanylmeth0xy)(2-meth0xy-eth0xy)-6,7-dihydr0-pyrimid0[6,1-
a]is0quinolin0ne.
This compound is prepared Via general method F using intermediate 6 and 1-bromomethoxy-
, KI was not used in this experiment.
Compound 130: 2-((S)-1 - [1 ,4 ]di0xanylmeth0xy)-9 -(2-eth0xy-eth0xy)-6 ,7 -dihydr0-pyrimid0 [6 ,1 -
a]is0quinolin0ne.
This compound is prepared Via general method F using intermediate 6 and 1-bromoethoxy-
ethane, K1 was not used in this experiment.
Compound 131: 9-cyclopropylmethoxy((S)-1 -[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1 -
a]isoquinolinone.
This compound is prepared Via general method F using intermediate 6 and bromomethyl-
cyclopropane, K1 was not used in this ment.
Compound 132: 2-((S)[1,4]dioxanylmethoxy)(2-fluoro-ethoxy)-6,7-dihydro-pyrimido[6,1-
a]isoquinolinone.
This compound is prepared Via general method F using intermediate 6 and 1-bromofluoro-
ethane, K1 was not used in this experiment.
Compound 133: 2-((S) [1 ,4]dioxanylmethoxy) [3 -(2-methoxy-ethoxy)-propynyl]-6,7-dihydro-
do [6,1 -a]isoquinolinone.
Synthesis fiJlly bed above.
Compound 134: 2-((S)[1,4]dioxanylmethoxy)[3-(2-ethoxy-ethoxy)-propynyl]-6,7-dihydropyrimido
[6,1 -a]isoquinolinone.
[00398] This compound is prepared Via general method K using intermediate 21 and 1-bromoethoxy-
ethane.
Compound 135: [1 ,4]dioxanylmethoxy) [3 -(2-fluoro-ethoxy)-propynyl]-6,7-dihydro-
pyrimido [6,1 -a]isoquinolinone.
[00399] This compound is prepared Via general method K using intermediate 21 and 1-bromofluoro-
ethane.
Compound 136: 9 -(2,2-dimethyl-propoxymethyl)((S) [1 ,4]dioxanylmethoxy)-6,7-dihydro-
do [6,1 -a]isoquinolinone.
[00400] This compound is prepared Via general method E using ediate 9, in a mixture of DME/HZO
(2/1), in a ave at 120 °C for 20 min and intermediate 17.
Compound 137: ohexyloxymethyl—2-((S)-1 -[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1 -
a]isoquinolinone.
WO 92791
This compound is prepared Via general method E using intermediate 9 and potassium
cyclohexyloxymethyltrifluoroborate in a mixture of DME/HZO (2/ 1), in a ave at 120 °C for 20 min.
Compound 138: 9-cyclopropylmethoxymethyl-Z-((S) [1 ,4]dioxanylmethoxy)-6,7-dihydro-
pyrimido [6,1 -a]isoquinolinone.
This compound is prepared Via general method E using intermediate 9, in a e of DME/HZO
(2/ 1), in a microwave at 120 °C for 20 min and intermediate 18.
Compound 139: 2-((S)[1 ,4]dioxanylmethoxy)(tetrahydro-pyranylmethoxy)-6,7-dihydro-
pyrimido [6,1 -a]isoquinolinone.
This compound is prepared Via general method F using intermediate 6 and 2-bromomethyl-
tetrahydro-pyran, KI was not used in this experiment.
nd 140: 2-((S) [1 ,4 ]dioxanylmethoxy)-9 -(3 -hydroxy-butyl)-6 ,7 -dihydro-pyrimido [6 ,1 -
a]isoquinolinone.
07)K/ OKE/o 05/0
0 0 O
Step 1 Step 2
O N 0%N 0%N
OTf §
Intermediate 9 Intermediate 26 Compound 140
Step I .' 2-((S)-I -[I,4]Dt0xanylmeth0xy)-9—(3-hydr0xy-but—I -ynyl)-6, 7-dihydr0-pyrtmtd0[6,1 -
a]isoquinolin0ne (Intermediate 26).
ediate 26 was prepared Via general method G using intermediate 9 and but-3 -ynol, the
crude product was used in the next step without characterization.
Step 2: -I -[I,4]dt0xanylmeth0xy)(3-hydr0xy-butyl)-6, 7-dihydr0-pyrimtd0[6,1 -a]ts0quinoltn0ne
(Compound 140).
] Compound 140 was prepared Via general method I using intermediate 26.
Compound 141: 9-(4,4-dimethy1-penty10xy)—2-((S)-1 -[1,4]di0xany1meth0xy)-6,7-dihydr0-pyrimid0[6,1 -
a]is0quin01in0ne.
O O
I| |
O N —> j:
O N
OH OW
Intermediate 6 Compound 141
Intermediate 6 (0.1 g, 0.303 mol, 1 eq.), 4,4-dimethy1—pentan01 (35 mg, 0.303 mmol, 1 eq.)
and PPh3 (95 mg, 0.363 mmol, 1.2 eq.) were suspended in 1,4-di0xane (5 mL) and the mixture was degassed
with N2. DIAD (0.065 mL, 0.333 mmol, 1.1 eq.) was added dropwise and the reaction was stirred at RT for 2
h. The reaction mixture was evaporated to dryness and the residue was purified by preparative TLC eluting
with EtOAc to give compound 141.
(H, CDC13) 5 ppm 7.70 - 7.58 (1 H, d), 6.95 - 6.82 ( 1 H, d), 6.77 (1 H, s), 6.27 (1 H, s), 4.50 - 4.32 (2 H,
m), 4.38- 4.15 (2 H, m), 4.05 - 3.92 (3 H, m), 3.92 - 3.60 (5 H, m), 3.55 - 3.42 (1 H, t), 3.05 - 2.92 (2 H, m),
1.85 - 1.70 (2 H, m), 1.40 - 1.30 (2 H, m), 0.92 (9 H, s)
MW (calcd): 428.5; MW (obsd): 429.2 (M+1)
Compound 142: 2-((S)[1,4]di0xany1meth0xy)(3-meth0xymethy1-penty1)-6,7-dihydr0-
do [6,1 -a]is0quin01in0ne.
O O O
b0 b0 b0
O/ O/ 0’-
Step 1 Step 2
N / _ ,.
OAN I 31/ _
I i/ I
O N O N
% Q
OH 0\
Intermediate 25 Intermediate 27 Compound 142
Step I .' 2-((S)-I -[I ,4]Dt0xanylmeth0xy)(3-meth0xymethyl—pent—I -ynyl)-6, dr0-pyrtmtd0[6,1 -
ajtsoqutnoltn0ne (Intermediate 2 7)
[00407] Intermediate 27 is prepared via general method H using intermediate 25.
MW ): 424.5; MW (obsd): 425.2 (M+1)
Step 2: -I -[1,4]dioxan-Z-ylmethoxy)-9— (3-melh0xy-4—melhyl—penlyl)-6, 7-dihydr0-pyrimid0[6, I -
a]isoquinolin0ne (Compound 142).
] Compound 142 is prepared Via general method I using intermediate 27.
Compound 143: 9-(3-cyclopropyl-propoxy)((S)-1 -[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1 -
a]isoquinolinone.
OQ OQ
0} O}
N / N /
0*N I I
—’ 0%N
OH 0%
Intermediate 6 nd 143
Intermediate 6 (2.12 g, 2.42 mol, 1 eq.), 4,4-dimethyl-pentanol (0.77 g, 7.71 mmol, 1.2 eq.)
and PPh3 (2.02 g, 7.71 mmol, 1.2 eq.) were suspended in 1,4-dioxane (50 mL) and the mixture was degassed
with N2. DIAD (1.56 mL, 7.71 mmol, 1.1 eq.) was added dropwise and the reaction was stirred at RT for 2 h.
The reaction mixture was quenched with brine and extracted with EtOAc, the organic phase was dried over
MgSO4 and ated to dryness. Compound 143 was obtained by purification by flash chromatography on
silica gel, eluting from 60 to 100% EtOAc/H.
(1H, CDC13) 5 ppm 7.66 - 7.60 (1 H, m), 6.91 - 6.86 (1 H, m), 6.80 - 6.76 (1 H, m), 6.28 (1 H, s), 4.48 - 4.35
(2 H, m), 4.24 — 3.95 (1 H, m), 3.91
- 4.17 (2 H, m), 4.11 - 4.04 (2 H, m), 4.02 - 3.61 (5 H, m), 3.54 - 3.45 (1
H, m), 3.03 — 2.94 (2 H, m), 1.98 - 1.88 (2 H, m), 1.45 - 1.36 (2 H, m), 0.78 - 0.66 (1 H, m), 0.50 - 0.43 (2 H,
m), 0.09 - 0.03 (2 H, m)
MW (calcd): 412.5; MW (obsd): 413.5
Compound 145: 9-cyclohexylamino((S)-1 -[1,4]dioxanylmethoxy)-6,7 -dihydro-pyrimido [6,1 -
a]isoquinolinone.
This compound is ed Via general method J using intermediate 13 and cyclohexanone.
Compound 146: 2-((S)[1,4]dioxanylmethoxy)—9-(3-hydroxy-4,4-dimethyl-pentyl)-6,7-dihydropyrimido
[6,1 -a]isoquinolinone.
$0 $0 o
O/E /E
O 0/5
Step 1 Step 2
0%N 0%N 0%N
OTf §
Intermediate 9. Intermediate 28 Compound 146
Step I .' 2-((S)-I -[I ,4]Di0xanylmeth0xy)(3-hydr0xy-4,4-dt'methyl—pent—I -ynyl)-6, 7-dt'hydr0-
pyrtmtd0[6,1 -a]is0qutnoltn0ne (Intermediate 28).
Intermediate 28 is prepared Via l method G using intermediate 9.
MW (calcd): 424.5; MW (obsd): 425.4 (M+1)
Step 2: 2-((S)-I -[I ,4]dioxan-Z-ylmethoxy)(3-hydr0xy-4, thyl—pentyD-6, 7-dt'hydr0-pyrt'mt'd0[6,1 -
a]isoquinolin0ne (Compound 146).
Compound 146 is prepared Via general method I using intermediate 28.
Compound 147: opentylmethoxymethyl-Z-((S) [1 ,4]dioxanylmethoxy)-6,7-dihydro-
pyrimido [6,1 -a]isoquinolinone.
This compound is ed Via general method E using intermediate 9, in a mixture of DME/HZO
(2/ 1), in a microwave at 120 °C for 20 min and intermediate 19.
C0mpound 148: 2-((S)[1,4]dioxanylmethoxy)—9-(3 -methoxy—butyl)-6 ,7 -dihydro-pyrimido [6 ,1 -
a]isoquinolinone.
(La/O 0/} 0/}
Ké/o 5/0
0 O 0
Step 1 Step 2
j: —' N —' N I
| | |
O N CAN CAN
% %
OH 0\
ediate 26 Intermediate 29 Compound 148
Step I .' 2-((S)-I -[I ,4]Di0xanylmeth0xy)-9—(3-meth0xy-but—I -ynyl)-6, 7-dt'hydr0-pyrt'mt'd0[6,1 -
a]isoquinolin0ne (Intermediate 29)
ediate 29 is prepared Via general method H using intermediate 26.
MW ): 396.4; MW (obsd): 397.2 (M+1)
Step I .' 2-((S)-I -[I ,4]dioxan-Z-ylmethoxy)(3-methoxy-butyl)-6, 7-dthydro-pyrt'mtdo[6,1 -a]isoqutnoltn
one (Compound 148)
Compound 148 is prepared Via general method I using intermediate 29.
Compound 149: [1 ,4]dioxanylmethoxy)(3 lamino-propyl)-6,7 -dihydro-pyrimido [6,1 -
a]isoquinolinone
O O O
K/O K/O K/O
; ; ;
0 0 O
Step 1 Step 2
N / —, N / —, N /
0%N I 0%N I 0%N I
OTf § H
N \©
Intermediate 9 Intermediate 30 Compound 149
Step I .' -I -[I,4]Dtoxanylmethoxy)-9—(3-phenylamt'no-prop-I -ynyl)-6, 7-dthydro-pyrt'mtdo[6,1 -
a]isoquinoltnone (Intermediate 30)
Intermediate 30 is prepared Via general method G using intermediate 9 and phenyl-prop-Z-ynyl-
amine.
MW (calcd): 443.5; MW (obsd): 444.2 (M+1)
Step 2: 2-((S)-I -[I , 4]dioxan-Z-ylmethoxy)(3-phenylamtno-propyl)-6, 7-dthydro-pyrt'mtdo[6,1 -
a]isoquinoltnone (Compound 149)
Compound 149 is prepared Via general method I using intermediate 30.
Compound 150: -1 -[1,4]dioxanylmethoxy)(4-hydroxy-pentyl)-6,7 -dihydro-pyrimido [6,1 -
a]isoquinolinone.
moK/ (LE/o (Li/o
O O 0
Step 1 Step 2
CAN CAN o//I\N OH
OTf §
Intermediate 9 Intermediate 31 Compound 150
Step I .' 2-((S)-I -[I ,4]Dt'oxanylmetnoxy)(4—hydroxy-pent—I -ynyl)-6, 7—dt'nydro-pyrt'mt'do[6,1 -
a]isoquinolinone (Intermediate 3])
Intermediate 31 was prepared Via general method G using intermediate 9, -ynol, iPrZNH
as base and THF as solvent.
MW (calcd): 396.4; MW (obsd): 397.2 (M+1)
Step 2: 2-((S)-I -[I ,4]dt'oxanylmetnoxy)(4—hydroxy-pentyl)-6, 7—dt'nydro-pyrt'mt'do[6,1 -a]t'soqut'nolt'n
one (Compound 150)
[00419] nd 150 was prepared Via general method I using ediate 31.
Compound 151: 2-((S)[1 ,4]dioxanylmethoxy)(4-hydroxy-butyl)-6,7 -dihydro-pyrimido [6,1 -
a]isoquinolinone.
o 0/} 0
$0 0
_ $0
0,: 0,: ,2
Step 1 Step 2
Oék N O N O N
OTf Q OH
Intermediate 9 Intermediate 32 Compound 151
Step I .' 2-((S)-I -[I,4]Dtoxanylmetnoxy)(4—hydroxy-but—I -6, 7-dt'nydro-pyrt'mt'do[6,1 -
a]isoquinolinone (Intermediate 32)
Intermediate 32 was prepared Via general method G using intermediate 9, but-3 -ynol, iPrZNH
as base and THF as t.
(1H, CDC13) 8 ppm 7.70 - 7.65 (1 H, m), 7.45 - 7.35 (1 H, m), 7.34 (1 H, s), 6.35 (1 H, s), 4.50 - 4.32 (2 H,
m), 4.28 - 4.10 (2 H, m), 4.05 - 3.90 (1 H, m), 3.95 - 3.60 (7 H, m), 3.55 - 3.40 (1 H, m), 3.05 - 2.90 (2 H,
m), 2.80 - 2.65 (2 H, m), 2.00 - 1.80 (1 H, m)
MW (calcd):382.4; MW : 383.2 (M+1)
Step 2: 2-((S)-I -[I,4]dtoxanylmetnoxy)(4-nydroxy-butyl)-6, 7—dt'nydro-pyrt'mt'do[6, I -a]t'soqut'nolt'none
(Compound 15]).
Compound 151 was prepared Via general method I using intermediate 32.
Compound 152: 9-(cyclohexyl-methyl—amino)((S)[1,4]dioxanylmethoxy)-6,7-dihydropyrimido
[6,1 -a]isoquinolinone.
o ON
K/o K/O
o’é /E
N ’ N ’
| |
0*“ 01“
Q Q
N N
H |
nd 147 nd 152
Mel (0.007 mg, 0.11 mmol, 1.2 eq.) was added to compound 147 (38 mg, 0.092 mmol, 1 eq.) and
NaH (6 mg, 0.15 mmol, 1.6 eq.) in DMF (5 mL) and the reaction was stirred at RT for 16 h. Some more NaH
(6 mg, 0.15 mmol, 1.6 eq.) and Mel (0.07 mg, 0.11 mmol, 1.2 eq.) were added to the reaction mixture and it
was stirred for a fithher 2 days. The mixture was quenched with brine and ted with EtOAc. The organic
layers were dried over MgSO4 and evaporated to dryness. The residue was d by preparative HPLC-MS
to provide compound 152.
(H, CDC13) 5 ppm 7.57 - 7.50 (1 H, m), 6.71 (1 H, d), 6.53 (1 H, br. s.), 6.21 (1 H, s), 4.51 - 4.33 (2 H, m),
4.26 — 3.93 (1 H, m), 3.92
- 4.14 (2 H, m), 4.06 - 3.56 (6 H, m), 3.56 - 3.41 (1 H, m), 3.00 - 2.90 (2 H, m),
2.88 (3 H, s), 2.04 — 1.63 (2 H, m), 1.60 - 1.31 (5 H, m), 1.28 - 1.08 (1 H, m)
MW (calcd): 425.5; MW (obsd): 426.4
Compound 153: 9-(cyclohexylmethyl-amino)—2-((S)-1 -[1,4]dioxanylmethoxy)-6,7-dihydro-pyrimido[6,1 -
a]isoquinolinone.
This compound is ed via general method J using intermediate 13 and
cyclohexanecarbaldehyde.
Compound 154: 2-((S)[1,4]dioxanylmethoxy)[(tetrahydro-pyranylmethyl)-amino]-6,7-dihydropyrimido
[6,1 -a]isoquinolinone.
This compound is prepared via general method J using intermediate 13 and tetrahydro-pyran
carbaldehyde.
Compound 155: 2-((S)-1 -[1,4]dioxanylmethoxy)—9-(3-ethylhydroxy-pentyl)-6,7 -dihydro-pyrimido[6,1 -
a]isoquinolinone.
ofi ofi ofi
O/2 O/ 0/2
Step 1 Step 2
N’ —.— N/ _ . N,
o’/J\N I | |
o N o N
OTf Q
Intermediate 9 Intermediate 33 nd 155
Step I .' 2-((S)-I -[I ,4]Dt0xanylmeth0xy)(3-ethyl—3-hydr0xy-pent—I -ynyl)-6, 7—dthydr0-pyrtmtd0[6,1-
ajtsoqutnoltn0ne (Intermediate 33)
Intermediate 33 is prepared Via general method G using intermediate 9 and 3-ethy1-pentynol.
(1H, CDC13) 5 ppm 7.51 - 7.46 (1 H, m), 7.28 - 7.24 (1 H, m), 7.22 - 7.19 (1 H, m), 6.20 (1 H, s), 4.30 - 4.19
(2 H, m), 4.08 - 4.00 (2 H, m), 3.87 - 3.79 (1 H, m), 3.75 - 3.47 (5 H, m), 3.39 - 3.30 (1 H, m), 3.03 (1 H, br.
S), 2.88 - 2.80 (2 H, m), 1.746 - 1.56 (4 H, m), 0.97 (6 H, s)
MW (calcd): 424.5; MW (obsd): 425.5 (M+1)
Step 2: 2-((S)-I -[1,4]dioxan-Z-ylmethoxy)-9— (3ethylhydr0xy-pentyl)-6, dro-pyrt'mt'do[6, I -
ajtsoqutnoltn0ne (Compound 155).
Compound 155 is prepared Via general method I using ediate 33.
Compound 156: 2-((S)[1 ,4]dioxany1methoxy)(3 -hydroxy—3 -methy1-buty1)-6,7-dihydro-
pyrimido [6,1 quinolinone
o/\ o/\ 0
$0 o
_ K/o
O/2 O/2 0/2
Step 1 Step 2
i’ —> —>
I i’ I i’ I
O N O N O N
OTf Q
Intermediate 9 Intermediate 34 Compound 156
Step I .' 2-((S)-I -[I ,4]Di0xanylmeth0xy)-9 -(3-hydr0xymethyl—but—I -ynyl)-6, 7—dt'hydr0-pyrt'mt'd0[6,1 -
ajtsoqutnolin0ne (Intermediate 34)
Intermediate 34 is prepared Via general method G using intermediate 9 and 2-methyl-butyn
(H, CDC13) 5 ppm 7.58 (1 H, d), 7.38 - 7.33 (1 H, m), 7.32 - 7.29 (1 H, m), 6.32 (1 H, s), 4.43 - 4.32 (2 H,
m), 4.18 - 4.12 (2 H, m), 3.99 - 3.91 (1 H, m), 3.87 - 3.58 (5 H, m), 3.50 - 3.42 (1 H, m), 2.97 - 2.90 (2 H, m),
1.60 (6 H, s)
MW ): 396.4; MW (obsd): 397.3 (M+1)
Step 2: 2-((S)-I -[I ,4]dioxanylmethoxy)-9—(3-hydroxymethyl—butyZ)-6, 7—dt'nydro-pyrt'mt'do[6,1 -
a]isoquinolinone (Compound 156)
[00428] Compound 156 is ed Via general method I using ediate 34.
Compound 157 : 2-((S)-1 dioxanylmethoxy)(3 -hydroxy-pentyl)-6,7 -dihydro-pyrimido [6,1 -
a]isoquinolinone.
O O O
K/0 K/0 $0
0,: 0,: 0,:
Step 1 Step 2
j: —’ i —’
I | i |
O N O N O N
OTf %
Intermediate 9 Intermediate 35 Compound 157
Step I .' 2-((S)-I -[I ,4]Dioxanylmethoxy)(3-hydroxy-pent—I -ynyl)-6, 7—dt'nydro-pyrt'mt'do[6,1 -
a]isoquinolinone (Intermediate 35)
Intermediate 35 is prepared Via general method G using intermediate 9 and pentynol.
(1H, CDC13) 8 ppm 7.62 - 7.57 (1 H, m), 7.41 - 7.35 (1 H, m), 7.33 (1 H, s), 6.34 (1 H, s), 4.60 - 4.53 (1 H,
m), 4.45 - 4.33 (2 H, m), 4.20 - 4.14 (2 H, m), 4.00 - 3.92 (1 H, m), 3.88 - 3.59 (5 H, m), 3.51 - 3.42 (1 H, m),
2.99 - 2.90 (2 H, m), 1.90 - 1.74 (2 H, m), 1.07 (3 H, t)
Step 2: 2-((S)-I -[I ,4]dtoxanylmethoxy)-9—(3-nydroxy-pentyZ)-6, 7—dt'nydro-pyrt'mt'do[6,1 -a]t'soquinolt'n
one und 15 7)
[00430] Compound 157 is prepared Via general method I using intermediate 35.
Compound 1 58: 9-(2 ,2 -dimethyl-propoxy)((S)-1 -[1,4]dioxanylmethoxy)-6,7 -dihydro-pyrimido [6,1 -
a]isoquinolinone.
Synthesis fiJlly described above.
1 l3
WO 92791
Compound 159: 2-((S)— 1 -[1 ,4]di0xanylmeth0xy)(tetrahydr0-pyranylmeth0xy)-6,7-dihydr0-
pyrimido [6,1 -a]is0quinolin0ne.
This compound is prepared Via general method L with intermediate 6 and methanesulfonic acid
tetrahydro-pyranylmethyl ester.
Compound 160: 2-((S)-1 -[1,4]di0xanylmeth0xy)(4-hydr0xymethyl-pentyl)-6,7-dihydr0-
pyrimido [6,1 -a]is0quinolin0ne.
o/\ o 0
K/0 K/0 K/0
0,: ,2 ,2
Step 1 Step 2
N ’ " N ’ ’ N ’
OékN I OékN I OékN I
OTf Q OH
Intermediate 9 Intermediate 36 Compound 160
Step I .' 2-((S)-I -[I,4]Dt0xanylmeth0xy)(4—hydr0xymethyZ-pent-I -ynyZ)-6, 7-dihydr0-pyrimtd0[6,1 -
ajtsoqutnolin0ne (intermediate 36)
A Vial was charged with intermediate 9 (0.15 g, 0.324 mol, 1 eq.), 2-methyltrimethylsilanyl-
pentynol (66 mg, 0.389 mmol, 1.2 eq), CuI (2.5 mg, 0.013 mmol, 0.04 eq.), iPrZNH (0.41 mL, 2.92
mol, 9 eq.) and THF (2 mL). The solution was purged with Ar for 15 min., and Pd(PPh3)C12 (11 mg, 0.016
mmol, 0.05 eq.) was added with TBAF (0.39 mL, 0.39 mmol, 1.2 eq., 1M in THF). The Vial was sealed and
the reaction was heated to 80 °C for 16 h. The reaction mixture was evaporated to dryness and the crude
product was purified by preparative TLC eOH, 98/2] to afford intermediate 36 2-((S)[1,4]di0xan-
2-ylmeth0xy)(4-hydr0xymethyl-pentynyl)-6,7-dihydr0-pyrimid0 [6, 1 -a]is0quinolin0ne.
(1H, CDC13) 5 ppm 7.70 - 7.58 (1 H, m), 7.45 - 7.38 (1 H, m), 7.35 (1 H, s), 6.37 (1H, s), 4.50 - 4.30 (2 H, m),
4.28 - 4.15 (2 H, m), 4.05 - 3.95 (1 H, m), 3.95 - 3.55 (5 H, m), 3.55 - 3.40 (1 H, m), 3.05 - 2.95 (2 H, m),
2.62 (2 H, s), 1.39 (6 H, s)
MW (calcd): 410.5; MW (obsd): 411.4
Step 2: 2-((S)-I -[I,4]dt0xanylmeth0xy)(4-hydr0xy-4—methyl—pentyl)-6, dr0-pyrimtd0[6,1 -
ajtsoqutnolin0ne (Compound 160)
nd 160 is prepared Via general method I using intermediate 36.
Compound 161: [1,4]dioxanylmeth0xy)—9-(tetrahydr0-pyranylmeth0xymethyl)-6,7-dihydr0-
pyrimido [6,1 -a]is0quinolin0ne.
l 14
This compound is prepared via general method E using ediate 9 and potassium 4-
(tetrahydropyranylmethoxy)methyltrifluoroborate.
Compound 162: 2-([1 ,4]dioxanylmethoxy)methoxy-6,7 -dihydro-pyrimido[[6, 1 -a]isoquinolinone
H NJOLN/fio/ St—>ep1NfLNM©\
H M
Intermediate 1
Intermediate 37
0/fi [Step 2
Step 3 N /
CAN I
Compound 162 Intermediate 38
Step I .' I -[2-(3-meth0xy—phenyl)-ethyl]-pyrimidine-2,4,6—tri0ne (intermediate 3 7)
Sodium (236 mg, 10.2 mmol, 2 eq.) was added to degassed EtOH (18 mL), when sodium
dissolved completely, ethyl te (1.56 mL, 10.2 mmol, 2 eq.) was added and the reaction was d
for 1 h. Intermediate 1 (995 mg, 5.12 mol, 1 eq.) in EtOH (4 mL) was then added and the reaction was
refluxed for 1 day. The desired intermediate 37 1-[2-(3-methoxy-phenyl)-ethyl]-pyrimidine-2,4,6-trione
precipitated upon on of 2N s HCl, it was filtered and washed with H20 and finally dried.
(1H, DMSO-d6) 5 ppm 7.27 - 7.18 (1 H, m), 6.84 - 6.72 (3 H, m), 3.92 - 3.83 (2 H, m), 3.75 (3 H, s), 3.62 (2
H, s), 2.80 - 2.70 (2 H, m)
MW (calcd): 262.3; MW (obsd): 263.3 (M+1)
Step 2: 2-chlor0meth0xy-6, 7-dihydr0-pyrimid0[6,1 -a]isoquinolin0ne (intermediate 38)
Intermediate 37 (920 mg, 3.51 mol, 1 eq.) was heated in POC13 (5 mL) at 50°C for 2 days. The
les were evaporated under vacuum, the residue was dissolved in DCM and washed with a saturated
aqueous solution ofNaHC03, before drying over MgSO4. Evaporation of the organic phase gave intermediate
38 2-chloromethoxy—6,7-dihydro-pyrimido[6,1-a]isoquinolinone, which was used in the next step
without further purification.
(1H, CDC13) 6 ppm 7.73 - 7.66 (1 H, m), 6.98 - 6.90 (1 H, m), 6.85 - 6.80 (1 H, m), 6.69 (1 H, s), 4.00 - 4.20
(2 H, m), 3.91 (3 H, s), 3.04 (2 H, m)
Step 3: 2-([I ,4]di0xanylmelh0xy)melh0xy-6, 7—dihydr0-pyrimid0[6,1-a]is0quinolin0ne (compound
I 62)
ioxanyl-methanol (42 mg, 0.36 mol, 2 eq.) was dissolved in DCM (3 mL) with NaH
(14 mg, 0.36 mmol, 2 eq., 60% in mineral oil). After 30 min, intermediate 38 (50 mg, 0.18 mmol, 1 eq.) was
added to the mixture and the reaction was stirred at RT for 16h. The reaction mixture was evaporated to
dryness and the crude product was purified by preparative HPLC-MS to provide compound 162.
(H, CDC13) 8 ppm 7.68 - 7.62 (1 H, m), 6.95 - 6.87 (1 H, m), 6.82 - 6.77 (1 H, m), 6.29 (1 H, s), 4.51 - 4.35
(2 H, m), 4.26 — 3.92 (1 H, m), 3.91 — 2.94 (2
- 4.17 (2 H, m), 4.05 - 3.60 (8 H, m), 3.55 - 3.44 (1 H, m), 3.04
H, m)
MW (calcd): 344.4; MW (obsd): 345.0
Compound 163: [1,4]dioxanylmethoxy)(oxetanylmethoxy)-6,7-dihydro-pyrimido[6,1-
a]isoquinolinone.
This compound is prepared via general method L using intermediate 6 and methanesulfonic acid
oxetan-3 -ylmethyl ester.
Compound 164: yclopropyl-propoxy)((R)[1,4]dioxanylmethoxy)—6,7-dihydropyrimido[6,1 -
a]isoquinolinone.
A solution of intermediate 6 (1.15 g, 3.48 mol, 1 eq.) and opropanol (0.349 g, 3.48
mmol, 1eq.) in 1,4-dioxane was degassed with Argon for 10 min. PPh3 (1.096 g, 4.18 mmol, 1.2 eq.) was
added and the reaction mixture was degassed with Argon an onal 5 min. DIAD (0.745 mL, 3.83 mmol,
1.1 eq.) was added dropwise at 0°C. The reaction e was stirred at RT for 16 h. opropylpropan
01 (0.150 mg, 1.49 mmol, 0.43 eq.) and PPh3 (0.30 g, 1.14 mmol, 0.33 eq.) were added. The reaction mixture
was cooled to 0°C and DIAD (0.350 mL, 1.80 mmol, 5.2 eq.) was added. After 1 h at RT, the reaction
mixture was concentrated under vacuum and the crude product was purified by flash chromatography on
silica-gel to afford compound 164.
(1H, DMSO-dg) 5 ppm 7.93 (1H, d), 6.97-6.92 (2 H, m), 6.53 (1H, s), 4.24-4.23 (2H, m), 4.08 (2H,
t), 4.00 (2H, t), 3.98-3.74 (3H, m), 3.68-3.57 (2H, m), 3.51-3.48 (1H, m), 3.37 (1H, t), 2.96 (2H, t),
1.84-1.80 (2H, m), 1.36-1.30 (2H, m), 0.81-0.63 (1H, m), 0.42-0.39 (2H, m), 0.04-0.02 (2H, m)
MW (calcd): 412.5; MW (obsd): 413.0 (M+1)
C0mpound 1 65: [1 ,4 ]dioxanylmethoxy)-9 -(3 -methoxy-propyl) -6 ,7 -dihydro-pyrimido [6 ,1 -
a]isoquinolinone.
K/o K/o K/o
0/- 0/: /:
Step 1 Step 2
31/ —) —>
I 31/ I 31/ I
O N O N O N
OTf Q 0\
Intermediate 9 Intermediate 39 Compound 165
Step I .' 2-((S)-I -[I,4]Dt'oxanylmethoxy)(3-methoxy-prop-I -ynyl)-6, 7—dt'hydro-pyrtmtdo[6, I -
ajt'soqut'nolt'none (Intermediate 39)
] Intermediate 39 was ed Via general method G using intermediate 9 and 3-methoxy—propyne.
(1H, CDC13) 5 ppm 7.68 (1 H, d), 7.48 (1 H, d), 7.42 (1 H, s), 6.40 (1 H, s), 4.50 - 4.41 (2 H, m), 4.38 (2 H,
s), 4.23 (2 H, t), 4.05 - 3.98 (1 H, m), 3.89 - 3.70 (5 H, m), 3.55 - 3.50 (4 H, m), 3.03 (2 H, t)
MW (calcd): 382.4; MW (obsd): 383.4 (M+1)
Step 2: 2-((S)-I-[I,4]dtoxanylmethoxy)(3-methoxy-propyl)-6,7—dt'hydro-pyrt'mtdo[6,I-ajt'soqut'nolt'n
one (Compound 165)
Compound 165 was prepared Via general method I using intermediate 39.
1 5 C0mpound 1 66: 2-((S)-1 - [1 ,4 ]dioxanylmethoxy)-9 - [2 -(1 -hydroxy-cyclopentyl)-ethyl] -6,7-dihydro-
pyrimido [6,1 -a]isoquinolinone.
0/} o 0
$0 $0 K/o
O; 0,: ,2
Step 1 Step 2
N’ —’ N/ —’ N/
OAN I DAN I DAN I
% OH
Intermediate 9 Intermediate 40 nd 166
Step I .' 2-((S)-I -[I ,4]Dt'oxanylmethoxy)(I -hydroxy-cyclopentylethynyl)-6, 7—dt'hydro-pyrt'mt'do[6,1 -
ajt'soqut'nolt'none (Intermediate 40)
[00443] ediate 40 is prepared Via general method G using intermediate 9 and 3-methoxy—propyne.
(1H,CDC13)6 ppm 7.54 (1 H, d), 7.31 (1 H, d), 7.26 (1 H, s), 6.28 (1 H, s), 4.39 - 4.30 (2 H, m), 4.12 (2 H,
t), 3.95 — 3.91 (1 H, m), 3.82 — 3.58 (5 H, m), 3.50 (1 H, m), 3.16 (1 H, s), 2.89 (2 H, t), 2.05 - 1.98 (4 H, m),
1.90 — 1.70 (4H, m)
Step 2: 2-((S)-I -[I , 4]dioxanylmethoxy)[2-(1 -nydroxy-cyclopentyl)-ethyl]-6, 7—dtnydro-pyrt'mtdo[6,1 -
uinolinone (Compound 166)
Compound 166 was prepared Via l method I using intermediate 40.
Compound 167 : 2-((R)[1 ,4]Dioxanylmethoxy)-9 -(4-hydroxy-tetrahydro-pyranylethynyl)-6,7 -
dihydro-pyrimido[6,1 -a]isoquinolinone.
This compound is prepared Via general method G using intermediate 10 and 4-Ethynyl—tetrahydro-
pyranol.
Compound 168: 2-((R)-1 - [1 ,4]Dioxanylmethoxy)-9 -(3 -methoxy-propyl)-6 ,7 -dihydro-pyrimido [6 ,1 -
a]isoquinolinone
#0 #0 3"
O O 0
Step 1 Step 2
N ’ —> N ’ —> N ’
OAN I OAN I OAN I
OTf % 0\
ediate 10 Intermediate 41 Compound 168
Step I .' 2-((R)-I -[I,4]Dtoxanylmethoxy)—9—(3-methoxy-prop-I -ynyZ)-6, 7—dihydro-pyrtmtdo[6, I -
a]isoquinoltnone (Intermediate 40)
Intermediate 41 is prepared Via l method G using intermediate 10 and 3-methoxy-propyne.
(1H, CDC13) ppm 7.56 (l H, d), 7.48 (l H, d), 7.33 (l H, s), 6.27 (l H, s), 4.32 - 4.27 (2 H, m), 4.23 (2 H,
s), 4.08 (2 H, t), 3.88 - 3.85 (l H, m), 3.76 - 3.49 (5 H, m), 3.40 - 3.34 (4 H, m), 2.90 (2 H, t)
Step 2: 2-((R)-I-[I,4]dtoxanylmethoxy)(3-methoxy-propyZ)-6,7—dihydro-pyrtmtdo[6,I-ajt'soqut'nolt'n
one (Compound 165)
[00447] Compound 168 is prepared Via general method I using intermediate 41.
Compound 169: 2-((R)[1,4]Dioxanylmethoxy)[2-(1-hydroxy-cyclopentyl)-ethyl]-6,7-dihydropyrimido
[6,1 -a]isoquinolinone
ofi 0% 0%
50 50 50
O O 0
Step 1 Step 2
N / —- N / —» N /
A ' A ' A '
O N O N O N
Intermediate 10 Intermediate 42 Compound 169
Step I .' 2-((S)-I -[I,4]Di0xanylmelh0xy)(I -hydr0xy-cyclopenZJ/ZelhynyD-d 7—dihydr0-pyrl'ml'd0[6,1 -
a]isoquinolin0ne mediate 42)
] ediate 42 is prepared Via general method G using intermediate 10 and 1-Ethyny1—
cyclopentanol.
(1H, CDC13) 8 ppm 7.47 (1 H, d), 7.25 (1 H, d), 7.20 (1 H, s), 6.22 (1 H, s), 4.32 - 4.24 (2 H, m), 4.05 (2 H,
t), 3.88 — 1.90 (4H, m), 1.85
- 3.85 (1H, m), 3.77 - 3.52 (5 H, m), 3.38 (1H, t), 2.83 (2 H, t), 2.02 - 1.67 (4H,
Step 2: 2-((R)-I -[I,4]Di0xanylmelh0xy)(I -hydr0xy-cyclopenZJ/ZelhynyD-d dr0-pyrl'ml'd0[6,1 -
a]isoquinolin0ne (Compound 169)
Compound 169 is prepared Via general method I using intermediate 42.
Compound 170: 2-((S)[1,4]Dioxany1methoxy)(2-propoxy-ethoxy)-6,7-dihydro-pyrimido[6,1-
a]isoquinolinone
O O
N / N ’
0%N I I
—> 0%N
/\/O\/\
OH O
Intermediate 6 Compound 170
Intermediate 6 (0.15 g, 0.45 mol, 1 eq.), 2-Propoxy—ethanol (63 ”L, 0.55 mmol, 1.2 eq.) and
PPh3 (144 mg, 0.55 mmol, 1.2 eq.) were suspended in 1,4-dioxane (5 mL) and the mixture was degassed with
N2. DIAD (0.108 mL, 0.55 mmol, 1.2 eq.) was added and the reaction was stirred at RT overnight. 0.5 eq. of
DIAD and PPh3 were added, and the reaction mixture was stirred at room temperature for an extra 2h.
Reaction mixture was diluted with brine, extracted with EtOAc, dried over MgSO4 and concentrated. Crude
product was purified on silicagel column to give compound 170.
Compound 171: 2-((S)-1 -[1,4]Dioxanylmethoxy)—9-(2-isopropoxy-ethoxy)-6,7 -dihydro-pyrimido [6,1 -
a]isoquinolinone
Q Q
o/ 0
ediate 6 Compound 171
Intermediate 6 (0.15 g, 0.45 mol, 1 eq.), 2-isopropoxy-ethanol (63 uL, 0.55 mmol, 1.2 eq.) and
PPh3 (144 mg, 0.55 mmol, 1.2 eq.) were suspended in 1,4-dioxane (5 mL) and the mixture was ed with
N2. DIAD (0.108 mL, 0.55 mmol, 1.2 eq.) was added and the reaction was stirred at RT for 5 h. 0.5 eq. of
DIAD and PPh3 were added, and the on mixture was stirred at room temperature overnight. Reaction
mixture was diluted with brine, extracted with EtOAc, dried over MgSO4 and concentrated. The crude
product was purified on silicagel column to give compound 171.
Compound 172: 2-((R)[1 ,4]Dioxanylmethoxy)-9 -(2-propoxy-ethoxy)-6,7 -dihydro-pyrimido [6,1 -
a]isoquinolinone
0 5/0
0 O
O N ’ 0%N
/\/O\/\
OH O
ediate 7 Compound 172
Intermediate 7 (0.25 g, 0.76 mol, 1 eq.), 2-Propoxy-ethanol (105 ”L, 0.91 mmol, 1.2 eq.) and
PPh3 (238 mg, 0.91 mmol, 1.2 eq.) were suspended in 1,4-dioxane (10 mL) and the mixture was degassed
with N2. DIAD (0.180 mL, 0.91 mmol, 1.2 eq.) was added and the reaction was stirred at RT overnight. 0.3
eq. of DIAD and PPh3 were added, and the reaction mixture was stirred at room temperature for an extra 24h.
Reaction mixture was d with brine, extracted with EtOAc, dried over MgSO4 and concentrated. Crude
t was purified on silicagel column to give compound 172.
nd 173: 2-((R)-1 -[1,4]Dioxanylmeth0xy)—9-(2-is0pr0p0xy-eth0xy)-6,7 -dihydr0-pyrimid0 [6,1 -
a]is0quin01in0ne
o/\ o/\
5O 5O
O O
N / N/
OAN | |
—> 02‘
OH ONOY
Intermediate 7 Compound 173
] Intermediate 7 (0.25 g, 0.76 mol, 1 eq.), r0p0xy—ethanol (105 ”L, 0.91 mmol, 1.2 eq.) and
PPh3 (238 mg, 0.91 mmol, 1.2 eq.) were suspended in 1,4-di0xane (10 mL) and the mixture was ed
with N2. DIAD (0.180 mL, 0.91 mmol, 1.2 eq.) was added and the on was stirred at RT for 5 h. 0.3 eq.
0f DIAD and PPh3 were added, and the reaction mixture was stirred at room temperature overnight. Reaction
mixture was diluted with brine, extracted with EtOAc, dried over MgSO4 and trated. Crude product
was purified on silicagel column to give compound 173.
Compound 174: 2-((S)[1,4]Dioxanylmeth0xy)—9-(4-meth0xy-butyl)-6,7-dihydr0-pyrimid0[6,1-
a]is0quin01in0ne
Step I .' potassium 3-melhoxy-propyl—Zrfluoroborare
/O\/\/Br /O\/\/BF3K
Intermediate 43
In a 2-neck round bottom flask equipped with a reflux condenser and an addition funnel was
charged with Mg (471 mg, 19.20 mol, 3 eq.) and EtzO (2 mL) under N2. One drop of neat (2-br0m0-ethyl)-
cyclopropane was added followed by two drops of dibromoethane. Once the 1St bubbles appeared, 1-Br0m0-
3-methoxy-propane (1 g, 6.54 mol, 1 eq.) in EtZO (10 mL) was added dropwise. Upon completion of the
addition, the resulting suspension was stirred at RT for 1 h. In a separate flask, purged with N2, a solution
made of B(OMe)3 (1.1 mL, 9.81 mmol, 1.5 eq.) in THF (12 mL) was cooled to -78 °C. To this solution, the 3-
methoxy-propyl magnesium bromide suspension was added dropwise via a double ended needle. The mixture
was d to stir for 1 h at -78 °C and then was warmed to RT for 1 h. After cooling the mixture to 0 °C, a
saturated aqueous on of KHFZ (5.8 mL, 4.5 M, 4.1 eq.) was added dropwise and the reaction e
was allowed to warm to RT. After 30 min, the solution was concentrated in-vacuo. The dried solids were
triturated with hot acetone and filtered to remove inorganic salts. The resulting filtrate was concentrated and
the solid residue was ated with Et20. Potassium 3-methoxy-propyl-trifluoroborate, intermediate 43, was
filtered and dried in-vacuo.
(1H, DMSO-d6) 5 ppm 3.19 — 3.13 (5 H, m), 1.38 — 1.29 (2 H, m), -0.1 - 0.19 (2 H, m)
Step 2: 2-((S)-I-[I,4]Dioxanylmeth0xy)(4—melh0xy-bulyl)-6,7-dihydr0-pyrimid0[6,I-ajisoquinolin
Compound 174 is prepared Via general method E using intermediates 9 and 43.
[00456] Table 11: Mass spectral data of the Compounds of the Invention
MW: Molecular weight calc: ated obs: ed
Structures Name MW MW
(calc) 0(bsd)
9 -Allyloxy—2-([1,4]dioxan
ylmethoxy)-6,7 -dihydro-
pyrimido[6, 1 -a] isoquinolin
2-( [1 ,4 ]Dioxanylmethoxy)-9 -
pyridin-3 -yl-6,7 -dihydropyrimido
[6, 1 -a] isoquinolin
2-( [1 ,4 ]Dioxanylmethoxy)-9 -
pyridinyl-6,7 -dihydropyrimido
[6, 1 -a] isoquinolin
WO 92791
2-[2-([1,4]Dioxan
ylmethoxy)—4-0x0-6,7-dihydr0-
4H-pyrimid0 [6,1 -a]isoquinoliny1] -benzonitrile
3-[2-([1,4]Dioxan
ylmethoxy)—4-0x0-6,7-dihydr0-
4H-pyrimid0 [6,1 -a]isoquinoliny1] -benzonitrile
[1,4]Dioxan
ylmethoxy)—4-0x0-6,7-dihydr0-
4H-pyrimid0 [6,1 -a]isoquinoliny1] -benzonitrile
[2-([1,4]Dioxany1meth0xy)-
4-0x0-6,7-dihydr0-4H-
pyrimid0[6,1-a]isoquinolin
yloxy]—acet0nitrile
2-([1 ,4]Dioxany1meth0xy)-9 -
(0xaz01—2-y1meth0xy)-6,7-
dihydro-pyrimid0[6, 1 -
a]isoquinolin0ne
Structures Name
(calc)
2-([1 ,4]Dioxany1meth0xy)-9 -
(pyridin-Z-ylmethoxy)-6,7-
dihydro-pyrimid0[6, 1 -
a]isoquinolin0ne
9 -(3 ,5 0r0-pheny1)
([1,4]dioxany1meth0xy)-6 ,7 -
o-pyrimid0[6, 1 -
a] isoquinolin0ne l(0)
9 -B enzofuran-2 -y1
([1,4]dioxany1meth0xy)-6,7-
dihydro-pyrimid0[6, 1 -
a]isoquinolin0ne
2-[2-([1,4]Dioxan
ylmethoxy)—4-0x0-6,7-dihydr0-
12 4H-pyrimid0[6,1-a]isoquinolin-
9-y1]-ind01e-1 -carb0xylic acid
tert-butyl ester
2012/076275
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
(1H-ind01—2-y1)-6 ,7 -dihydr0-
pyrimido[6, 1 -a] isoquinolin
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
(6-meth0xy-pyridin-3 -y1)—6,7 -
dihydro-pyrimid0[6, 1 -
a] nolin0ne
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
(6-triflu0r0methy1—pyridin-3 -
y1)-6,7-dihydr0-pyrimid0[6,1-
a] isoquinolin0ne
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
(3 -methy1—3 H-imidaz01
1 6 ylethynyl)-6,7-dihydr0-
pyrimido[6, 1 -a] isoquinolin
9 -(5 -tert-Buty1—
o [1,2,4]0xadiaz01—3 -y1meth0xy)-
17 2-([1,4]dioxany1meth0xy)—
6,7-dihydr0-pyrimido[6,1-
a] isoquinolin0ne
-[2-([1,4]Di0xan
oxy)—4-0x0-6,7-dihydr0-
18 4H-pyrimid0 [6,1 -a]isoquin01in-
9-y1] -pyridinecarb0xy1ic acid
methylamide
2-( [1 ,4 ]Di0xany1meth0xy)-9 -
pentyny1-6 ,7 -dihydr0-
pyrimido[6, 1 -a] is0quin01in
2-( [1 ,4 ]Di0xany1meth0xy)-9 -
(2-pyridiny1—ethy1)—6,7-
dihydro-pyrimid0[6, 1 -
a] isoquinolin0ne
2-([1 ,4]Di0xany1meth0xy)-9 -
(2-pyrazin-2 -y1- ethy1)-6,7-
dihydro-pyrimid0[6, 1 -
a]isoquin01in0ne
2-( [1 ,4 ]Di0xany1meth0xy)-9 -
(1H-ind01—5 -y1)-6 ,7 -dihydr0-
do[6, 1 -a] is0quin01in
2-([1 ,4]Dioxany1meth0xy)-9 -
h0xy-pheny1)—6,7-
dihydro-pyrimid0[6, 1 -
a]isoquinolin0ne
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
(5 -meth0xy-pyridin-3 -y1)—6,7 -
dihydro-pyrimid0[6, 1 -
a] isoquinolin0ne
2-([1 ,4]Dioxany1meth0xy)-9 -
(1H-indaz01—5 -y1)-6,7-dihydr0-
pyrimid0[6,1-a]isoquinolin
2-([1 ,4]Dioxany1meth0xy)-9 -
(4-meth0xy-pheny1)—6,7-
dihydro-pyrimid0[6, 1 -
a]isoquinolin0ne
3-[2-([1,4]Dioxan
ylmethoxy)—4-0x0-6,7-dihydr0-
4H-pyrimid0 [6,1 -a]isoquinoliny1] -benzamide
-[2-([1,4]Dioxan
ylmethoxy)—4-0x0-6,7-dihydr0-
4H-pyrimid0 [6,1 -a]isoquinolin-
9-y1]flu0r0-benzamide
N—{3-[2-([1,4]Dioxan
ylmethoxy)—4-0x0-6,7-dihydr0-
imid0 [6,1 -a]isoquinoliny1] -pheny1} -acetamide
9 -Cyclopr0py1ethynyl
([1,4]dioxany1meth0xy)-6,7 -
dihydro-pyrimid0[6, 1 -
a]isoquinolin0ne
2-([1 ,4]Dioxany1meth0xy)-9 -
(1 -hydr0xy-
3 1 cyclopentylethyny1)-6,7-
o-pyrimid0[6, 1 -
a]isoquinolin0ne
WO 92791
2-([1,4]Dioxany1methoxy)
pyrimidin-5 --y16,7-d1hydro-
pyrimido[6, 1 a—]150qu1nolin
ohex-eny12-
([1 4,]dioxany1methoxy)-6,7-
d1hydro-pyr1m1do[6, 1-
a]1soqu1nolinone
2-([1 ,4]Dioxany1methoxy)
(1-methy1—1H-1ndoly1)-6,7-
d1hydro-pyr1m1do[6, 1-
a]1soqu1nolinone
2-([1 ,4]Dioxany1methoxy)
(6-methyl—pyridin-3 --y1)6,7-
d1hydro-pyr1m1do[6, 1-
a]1soqu1nolinone
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
pyridin-Z-ylethyny1-6,7-
dihydro-pyrimid0[6, 1 -
a] isoquinolin0ne
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
(3 -meth0xy-pr0p-1 -yny1)—6,7-
dihydro-pyrimid0[6, 1 -
a] isoquinolin0ne
-[2-([1,4]Dioxan
ylmethoxy)—4-0x0-6,7-dihydr0-
4H-pyrimid0 [6,1 -a]isoquinolin-
9-y1]-pentynenitrile
2-([1 xany1meth0xy)-9 -
(3 -hydr0xy—pr0pyny1)—6,7-
dihydro-pyrimid0[6, 1 -
a]isoquinolin0ne
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
(4-meth0xy—phenylethynyl)-6 ,7 -
o-pyrimid0[6, 1 -
a] isoquinolin0ne
WO 92791
Structures Name MW
(calc) (0
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
n-3 -ylethyny1-6 ,7 -
dihydro-pyrimid0[6, 1 -
a] isoquinolin0ne
4-[2-([1,4]Dioxan
ylmethoxy)—4-0x0-6,7-dihydr0-
4H-pyrimid0 [6,1 -a]isoquinolin-
9-y1]-N-methy1—benzamide
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
(3 -meth0xy-pheny1)—6,7 -
dihydro-pyrimid0[6, 1 -
a] isoquinolin0ne
9-(2-Ch10r0-pheny1)
([1,4]dioxany1meth0xy)-6,7 -
dihydro-pyrimid0[6, 1 -
a]isoquinolin0ne
Structures Name MW
(calc)
2-( [1 ,4 ny1methoxy)-9 -
(4-hydroxy-but-1 -6 ,7 -
dihydro-pyrimido[6, 1 -
a] isoquinolinone
9 -(1 ,5 -Dimethy1— 1 H-pyraz01-3 -
ylmethoxy)([1,4]dioxan
46 yhnethoxy)-6,7 -dihydro-
pyrimido[6, 1 -a] isoquinolin
I 2-( [1 ,4 ]Dioxany1methoxy)-9 -
(1 -methy1—1H-pyrazol—3 -
47 yhnethoxy)-6,7 -dihydro-
pyrimido[6, 1 -a] isoquinolin
2-( [1 ,4 ]Dioxany1methoxy)-9 -
(3 -methy1—[1,2,4]oxadiazol—5 -
48 yhnethoxy)-6,7 -dihydro-
pyrimido[6, 1 -a] isoquinolin
Structures Name MW
(calc) (0
2-([1 ,4]Dioxany1meth0xy)-9 -
(4-m0rpholiny1-pheny1)-6,7-
o-pyrimid0[6, 1 -
a]isoquinolin0ne
3-[2-([1,4]Dioxan
ylmethoxy)—4-0x0-6,7-dihydr0-
4H-pyrimid0 [6,1 -a]isoquinolin-
9-y1]flu0r0-benzamide
3-[2-([1,4]Dioxan
oxy)—4-0x0-6,7-dihydr0-
4H-pyrimid0[6,1-a]isoquinolin-
9-y1]—5-flu0r0-benzamide
9-(3 ,3 -Dimethy1—butyny1)
([1,4]dioxany1meth0xy)-6,7 -
dihydro-pyrimid0[6, 1 -
a]isoquinolin0ne
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
pyridinylethyny1-6 ,7 -
dihydro-pyrimid0[6, 1 -
a] isoquinolin0ne
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
(3 -methy1—isoxaz01—5 -
54 ylmethoxy)-6,7 r0-
pyrimido[6, 1 -a] isoquinolin
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
(3 -hydr0xy-3 -methy1—but
55 ynyl)—6,7-dihydr0-
pyrimido[6, 1 -a] isoquinolin
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
(2-meth0xy-pyridin-3 -y1)—6,7 -
dihydro-pyrimid0[6, 1 -
a] nolin0ne
2-([1 ,4]Dioxany1meth0xy)—
57 6,7-dihydr0-pyrimid0[6,1-
a]isoquinolin0ne
Structures Name
(calc)
9-(3,6-Dihydr0-2H-pyrany1)-
2-([1 ,4]dioxany1meth0xy)-
6,7-dihydr0-pyrimido[6,1-
a]isoquinolin0ne
-[2-([1,4]Dioxan
ylmethoxy)—4-0x0-6,7-dihydr0-
4H-pyrimid0 [6,1 -a]isoquinolin-
9-y1]-pyridinecarb onitrile
2-([1 ,4]Dioxany1meth0xy)-9 -
(6-isoprop0xy-pyridin-3 -y1)-
hydr0-pyrimido[6,1-
a]isoquinolin0ne
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
0xy—pyridin-3 -y1)-6 ,7 -
dihydro-pyrimid0[6, 1 -
a] isoquinolin0ne
Structures Name
(calc)
I O 2-( [1 ,4 ]Dioxany1meth0xy)-9 -
(6-m0rpholiny1-pyridin-3 -
y1)-6,7-dihydr0-pyrimid0[6,1-
a] isoquinolin0ne
9 -(2,3 -Dimeth0xy-phenyl)
([1,4]dioxany1meth0xy)-6 ,7 - ;I(NW)
dihydro-pyrimid0[6, 1 -
a] isoquinolin0ne
9 -(3 0meth0xy-
pyridiny1)( [1 ,4]dioxan
ylmethoxy)-6,7 r0- 456
pyrimido[6, 1 -a] isoquinolin
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
(2-methy1—pyridiny1)-6 ,7 -
dihydro-pyrimid0[6, 1 -
a] isoquinolin0ne
Structures Name
(calc)
3-[2-([1,4]Dioxan
ylmethoxy)—4-0x0-6,7-dihydr0-
4H-pyrimid0 [6,1 -a]isoquinolin-
9-y1]—isonicotin0nitrile
9 -(2,5 -Dimeth0xy-phenyl)
([1,4]dioxany1meth0xy)-6 ,7 -
dihydro-pyrimid0[6, 1 -
a] nolin0ne
2-([1 ,4]Dioxany1meth0xy)-9 -
(3,4,5,6-tetrahydr0-2H-
[1 ,2']bipyridiny1—5 '-y1)-6,7- 475
dihydro-pyrimid0[6, 1 -
uinolin0ne
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
(2-eth0xy—pyridin-3 -y1)-6 ,7 -
dihydro-pyrimid0[6, 1 -
a] isoquinolin0ne
Structures Name
(calc)
9 Dimeth0xy—pyridin-3 -
y1)([1 ,4]dioxan
70 ylmethoxy)-6,7 -dihydr0-
pyrimido[6, 1 -a] isoquinolin
4-[2-([1,4]Dioxan
ylmethoxy)—4-0x0-6,7-dihydr0-
4H-pyrimid0 [6,1 -a]isoquinolin-
9-y1]-nicotin0nitrile
9-tert-But0xymethy1—2-
([1,4]dioxany1meth0xy)-6,7 -
dihydro-pyrimid0[6, 1 -
a]isoquinolin0ne
2-( [1 ,4 ny1meth0xy)-9 -
(2-pyrrolidin-1 -y1-pyridin-3 -y1)-
6,7-dihydr0-pyrimido[6,1-
a] isoquinolin0ne
2-( [1 ,4 ]Di0xany1meth0xy)-9 -
(6-pyrr01idin-1 -y1-pyridin-3 -y1)-
6,7-dihydr0-pyrimido[6,1-
a] is0quin01in0ne
2-( [1 ,4 ny1meth0xy)-9 -
(5 -pheny1—oxaz01-2 -
ylmethoxy)-6,7 r0-
pyrimido[6, 1 -a] is0quin01in
9 -(5 -tert-Buty1—0xaz01—2-
ylmethoxy)([1,4]di0xan
ylmethoxy)-6,7 -dihydr0-
pyrimido[6, 1 -a] is0quin01in
9 -(5 -Cyclopr0py1—
[1 ,2,4] oxadiaz01-3 -y1meth0xy)-
2-([1 xany1meth0xy)-
6,7-dihydr0-pyrimido[6,1-
a]is0quin01in0ne
2-( [1 ,4 ]Di0xany1meth0xy)-9 -
(5 -ethy1— [1 ,2 ,4] oxadiaz01-3 -
ylmethoxy)-6,7 -dihydr0-
pyrimido[6, 1 -a] is0quin01in
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
(5 -methy1—[1,2,4]0xadiaz01—3 -
ylmethoxy)-6,7 -dihydr0-
pyrimido[6, 1 -a] isoquinolin
2-( [1 ,4 ny1meth0xy)-9 -
(5 -isopr0py1—[ 1 ,2,4]0xadiaz01—
3 -y1meth0xy)—6,7-dihydr0-
pyrimido[6, 1 -a] nolin
9 -Cyclopentylethyny1-2 -
([1,4]dioxany1meth0xy)-6,7 -
dihydro-pyrimid0[6, 1 -
a]isoquinolin0ne
9-Cyclohexy1ethyny1—2-
([1,4]dioxany1meth0xy)-6,7 -
dihydro-pyrimid0[6, 1 -
a]isoquinolin0ne
WO 92791
2-( [1 ,4 ]Dioxany1methoxy)-9 -
(3 -methy1—butyny1)-6,7 -
dihydro-pyrimido[6, 1 -
a] isoquinolinone
2-( [1 ,4 ]Dioxany1methoxy)-9 -
hexyny1—6 ,7 -dihydropyrimido
[6, 1 -a] isoquinolin
9 - [3 -(B enzyl-methyl—amino)-
propyny1]-2 -( [1 ,4]dioxan
yhnethoxy)-6,7 -dihydropyrimido
[6, 1 -a] isoquinolin
2-( [1 ,4 ]Dioxany1methoxy)-9 -
(3 -hydroxy-5 -methy1—hex
yny1)-6,7-dihydropyrimido
[6, 1 -a] nolin
2-( [1 ,4 ]Dioxany1methoxy)-9 -
(3 -hydroxy-but-1 -yny1)-6 ,7 -
dihydro-pyrimido[6, 1 -
a] isoquinolinone
ng Structures Name MW MW
(calc) (obsd)
9-Cyclopropy1—2-([1 ,4]dioxan-
2-y1methoxy)—6,7-dihydro-
pyrimido[6,1-a]isoquinolin
2-( [1 ,4 ]Dioxany1methoxy)-9 -
(3 -hydroxy-pentyny1)-6,7 -
dihydro-pyrimido[6, 1 -
a] isoquinolinone
2-( [1 ,4 ]Dioxany1methoxy)-9 -
(3 -hydroxymethy1—pent
yny1)-6,7-dihydropyrimido
[6, 1 -a] isoquinolin
2-( [1 ,4 ]Dioxany1methoxy)-9 -
(3 -ethy1—3 -hydroxy-pent
9 yny1)-6,7-dihydro-
do[6, 1 -a] isoquinolin
one I
2-( [1 ,4 ]Dioxany1methoxy)-9 -
(3 xy-3 -pheny1-but-1 -
92 yny1)-6,7-dihydropyrimido
[6, 1 -a] isoquinolin
9 -(3 -Benzylamino-prop-1 -
yny1)([1,4]dioxan
93 ylmethoxy)-6,7 ropyrimido
[6, 1 -a] isoquinolin
Structures Name
(calc) (obsd)
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
[(furan-Z-y1methy1)-amin0]—6,7-
dihydro-pyrimid0[6, 1 -
a] isoquinolin0ne
2-([1 ,4]Dioxany1meth0xy)-9 -
(1 -ethy1—1H-pyraz01y1)-6,7-
o-pyrimid0[6, 1 -
a]isoquinolin0ne
2-([1 ,4]Dioxany1meth0xy)-9 -
[1 -(3 -methy1—buty1)-1 H-
pyraz01y1]-6,7-dihydr0- 451
pyrimid0[6,1-a]isoquinolin
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
(5 -methy1—furany1)-6,7 -
dihydro-pyrimid0[6, 1 -
a] isoquinolin0ne
ures Name
(calc)
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
(3 -hydr0xy-hexyny1)-6 ,7 -
dihydro-pyrimid0[6, 1 -
a] isoquinolin0ne
9 -(3 ,5 -Dimethy1—1H-pyraz01—4-
y1)([1 ,4]dioxan
ylmethoxy)-6,7 -dihydr0-
pyrimido[6, 1 -a] isoquinolin
2-([1 xany1meth0xy)-9 -
(1 H-pyraz01y1)-6,7-dihydr0-
pyrimid0[6,1-a]isoquinolin
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
(1 -pr0py1—1H-pyraz01—4-y1)-6,7 -
dihydro-pyrimid0[6, 1 -
a] isoquinolin0ne
Structures Name
(calc)
(R)—1-[1,4]Dioxan
ylmethoxy)—4-0x0-6,7-dihydr0-
4H-pyrimid0 [6,1 -a]isoquinoliny1] -benzonitrile
2-[2-((S)—1-[1,4]Dioxan
ylmethoxy)—4-0x0-6,7-dihydr0-
imid0 [6,1 -a]isoquinolin-
9-y1]—benz0nitrile
9 -(5 -Cyclopr0py1—
[1 ,2,4] oxadiaz01-3 -y1meth0xy)-
2-((R)[1,4]dioxan
ylmethoxy)-6,7 -dihydr0-
pyrimido[6, 1 -a] isoquinolin
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
ethyny1-6 ,7 -dihydr0-
pyrimido[6, 1 -a] isoquinolin
2-([1 ,4]Dioxany1meth0xy)-9 -
pyrimidin-Z-ylethynyl-6,7-
dihydro-pyrimid0[6, 1 -
a]isoquinolin0ne
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
(3 -pheny1amin0-pr0pyny1)-
hydr0-pyrimido[6,1-
a] isoquinolin0ne
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
(3 -hydr0xy—3 -pyridin-3 -y1-
prop-1 -6,7-dihydr0-
pyrimido[6, 1 -a] isoquinolin
9-Cyclopenty10xymethy1—2-
([1,4]dioxany1meth0xy)-6,7 -
dihydro-pyrimid0[6, 1 -
a]isoquinolin0ne
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
(3 -meth0xymethy1—pent
yny1)-6,7-dihydr0-
pyrimido[6, 1 -a] isoquinolin
ng Structures Name MW MW
(calc) (obsd)
9-Cyclopr0py1ethyny1—2-((R)-1 -
[1 ,4]dioxany1meth0xy)-6,7-
dihydro-pyrimid0[6, 1 -
37 379
a]isoquinolin0ne II
2-((S)—1-[1,4]Dioxan
ylmethoxy)—9-(3 -methy1-but-1 -
ynyl)—6,7-dihydr0- 380 38 1
pyrimid0[6,1-a]isoquinolin
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
(3 -imidaz01— 1 -y1-pr0p-1 -yny1) -
4 1 8 1 9
6,7-dihydr0-pyrimido[6,1-
a] nolin0ne
9-(2-Cyclopropyl—ethyl)—2-((R)[1,4]dioxany1meth0xy)-
382 383
6,7-dihydr0-pyrimido[6,1-
a]isoquinolin0ne
9-Cyclopenty10xymethy1—2-
((R)—1-[1,4]dioxan
ylmethoxy)-6,7 -dihydr0-
pyrimid0[6,1-a]isoquinolin
2-( [1 ,4 ny1meth0xy)-9 -
(3 -hydr0xy—3 -pyridin-3 -y1-
propy1)-6 ,7 -dihydr0 -
pyrimido[6, 1 -a] isoquinolin
9 -A11y10xy—2-((R)
[1 xany1meth0xy)-6,7-
dihydro-pyrimid0[6, 1 -
a]isoquinolin0ne
9 -A11y10xy—2-((S)-1 -
[1 ,4 ]dioxany1meth0xy)-6,7 -
dihydro-pyrimid0[6, 1 -
a] isoquinolin0ne
2-((R)[1,4]Dioxan
ylmethoxy)(tetrahydr0-
pyrany10xymethy1)-6,7-
dihydro-pyrimid0[6, 1 -
a]isoquinolin0ne
2-( [1 ,4 ]Dioxany1meth0xy)-9 -
{3 - [(pyridin-3 -y1methy1)—
amino] 1 -yny1} -6,7 -
dihydro-pyrimid0[6, 1 -
a] isoquinolin0ne
2-((R)[1,4]Dioxan
ylmethoxy)-9 -penty1-6,7-
dihydro-pyrimid0[6, 1 -
a]isoquinolin0ne
9-Cyclopropylethynyl-Z-((S)-1 -
[1 ,4]dioxany1meth0xy)-6,7-
dihydro-pyrimid0[6, 1 -
a]isoquinolin0ne
9-(2-Cyclopropyl—ethyl)—2-((S)[1,4]dioxany1meth0xy)-
6,7-dihydr0-pyrimido[6,1-
a]isoquinolin0ne
: 2-((S)—1-[1,4]Dioxan
O/ oxy)-9 -(0xetan-3 -
124 yloxymethyl)—6,7-dihydr0- 400 401
| pyrimido[6, 1 -a] isoquinolin
O N one
2-((S)—1-[1,4]Dioxan
yhnethoxy)-9 -(3 -methyl-
oxetan-3 -y1methoxymethy1)-
6,7-dihydro-pyrimido[6,1-
a] isoquinolinone
-Dimethy1—buty1amino)-2 -
((S)[1,4]dioxan
yhnethoxy)-6,7 -dihydropyrimido
[6, 1 -a] isoquinolin
2-((S)—1-[1,4]Dioxan
yhnethoxy)(3 -hydroxy-4 -
methyl-penty1)-6 ,7 -dihydro-
pyrimido[6, 1 -a] isoquinolin
2-((S)—1-[1,4]Dioxan
oxy)—9-(2-ethy1—
hexylamino)-6,7-dihydro-
pyrimido[6,1-a]isoquinolin
2-((S)—1-[1,4]Dioxan
oxy)(2-methoxy—
ethoxy)-6 ,7 -dihydropyrimido
[6,1-a]isoquinolin
2-((S)—1-[1,4]Dioxan
ylmethoxy)-9 -(2-eth0xy—
ethoxy)-6 ,7 -dihydr0-
do[6, 1 -a] nolin
9-Cyclopr0py1meth0xy—2-((S)[1,4]dioxany1meth0xy)-
6,7-dihydr0-pyrimido[6,1-
a]isoquinolin0ne
2-((S)—1-[1,4]Dioxan
ylmethoxy)—9-(2-flu0r0-
ethoxy)-6 ,7 -dihydr0-
pyrimid0[6,1-a]isoquinolin
2-((S)—1-[1,4]Dioxan
ylmethoxy)-9 - [3 -(2-meth0xy—
ethoxy)-pr0pyny1]—6,7 -
dihydro-pyrimid0[6, 1 -
a] isoquinolin0ne
2-((S)—1-[1,4]Dioxan
ylmethoxy)—9 - [3 -(2-eth0xy-
ethoxy)-pr0pyny1]—6,7 -
dihydro-pyrimid0[6, 1 -
a] nolin0ne
2-((S)—1-[1,4]Dioxan
ylmethoxy)—9-[3-(2-flu0r0-
ethoxy)-pr0pyny1]—6,7-
dihydro-pyrimid0[6,1-
a]isoquinolin0ne
9 -(2,2-Dimethy1—
propoxymethy1)((S)
[1 ,4]dioxany1meth0xy)-6,7-
dihydro-pyrimid0[6, 1 -
a]isoquinolin0ne
9-Cyclohexyloxymethyl-Z-((S)[1,4]dioxany1meth0xy)-
6,7-dihydr0-pyrimido[6,1-
uinolin0ne
9-Cyclopropylmethoxymethyl-
2-((S)[1,4]dioxan
ylmethoxy)-6,7 -dihydr0-
pyrimid0[6,1-a]isoquinolin
2-((S)—1-[1,4]Dioxan
ylmethoxy)(tetrahydr0-
pyran-Z-ylmethoxy)—6,7-
dihydro-pyrimid0[6, 1 -
a]isoquinolin0ne
2-((S)—1-[1,4]Dioxan
ylmethoxy)(3 xy—
buty1)-6,7-dihydr0-
pyrimid0[6,1-a]isoquinolin
9 -(4 ,4 -Dimethy1—pentyloxy)
((S)[1,4]dioxan
yhnethoxy)-6,7 -dihydropyrimido
[6, 1 -a] isoquinolin
2-((S)—1-[1,4]Dioxan
yhnethoxy)-9 -(3 -methoxy—4-
methyl-penty1)-6 ,7 ropyrimido
[6, 1 -a] isoquinolin
9 -(3 propy1—propoxy)
((S)[1,4]dioxan
yhnethoxy)-6,7 -dihydro-
pyrimido[6, 1 -a] isoquinolin
9 -Cyclohexy1amino((S)— 1 -
[1 ,4]dioxany1methoxy)-6,7-
dihydro-pyrimido[6, 1 -
a]isoquinolinone
2-((S)—1-[1,4]Dioxan
ylmethoxy)(3 -hydroxy—4,4-
dimethyl—penty1)-6,7-dihydropyrimido
[6,1-a]isoquinolin
opentylmethoxymethyl-
2-((S)[1,4]dioxan
yhnethoxy)-6,7 -dihydropyrimido
[6,1-a]isoquinolin
2-((S)—1-[1,4]Dioxan
ylmethoxy)—9-(3 -methoxy—
-6,7-dihydro-
pyrimido[6,1-a]isoquinolin
2-((S)—1-[1,4]Dioxan
ylmethoxy)—9-(3 -pheny1aminopropy1
)-6 ,7 -dihydro -
pyrimido[6, 1 -a] isoquinolin
2-((S)—1-[1,4]Dioxan
ylmethoxy)(4-hydroxy—
penty1)-6 ,7 -dihydro-
pyrimido[6,1-a]isoquinolin
2-((S)—1-[1,4]Dioxan
ylmethoxy)(4-hydroxy—
buty1)-6,7-dihydropyrimido
[6,1-a]isoquinolin
2012/076275
9-(Cyclohexyl-methyl-amino)-
2-((S)[1,4]dioxan
yhnethoxy)-6,7 -dihydro-
pyrimido[6,1-a]isoquinolin
9-(Cyclohexylmethyl-amino)-2 -
((S)[1,4]dioxan
yhnethoxy)-6,7 -dihydropyrimido
[6, 1 -a] isoquinolin
2-((S)—1-[1,4]Dioxan
ylmethoxy)[(tetrahydropyrany1methyl
)-amino]-6,7-
dihydro-pyrimido[6, 1 -
a]isoquinolinone
2-((S)—1-[1,4]Dioxan
yhnethoxy)-9 -(3 -ethy1—3 -
hydroxy-penty1)-6 ,7 ro-
pyrimido[6, 1 -a] isoquinolin
ng Structures Name MW MW
(calc) (obsd)
2-((S)—1-[1,4]Dioxan
yhnethoxy)(3 -hydroxy-3 -
methyl-buty1)-6,7-dihydro- 400 40 1
pyrimido[6, 1 -a] isoquinolin
2-((S)—1-[1,4]Dioxan
ylmethoxy)(3 -hydroxy—
penty1)-6 ,7 -dihydro- 400 40 1
pyrimido[6, 1 -a] isoquinolin
9 -(2,2-Dimethy1—propoxy)
((S)[1,4]dioxan
yhnethoxy)-6,7 -dihydro- 400 40 1
pyrimido[6, 1 -a] isoquinolin
—1-[1,4]Dioxan
oxy)(tetrahydropyrany1methoxy
)—6,7- 28 29
dihydro-pyrimido[6, 1 -
a]isoquinolinone
2-((S)—1-[1,4]Dioxan
yhnethoxy)(4-hydroxy
methyl-penty1)-6 ,7 -dihydropyrimido
]isoquinolin
2-((S)—1-[1,4]Dioxan
ylmethoxy)(tetrahydropyrany1methoxymethyl
)-6,7-
dihydro-pyrimido[6, 1 -
a]isoquinolinone
2-([1 ,4]Dioxany1methoxy)-9 -
methoxy—6,7-dihydro-
pyrimido[6,1-a]isoquinolin
2-((S)—1-[1,4]Dioxan
yhnethoxy)-9 -(oxetan-3 -
yhnethoxy)-6,7 ro-
pyrimido[6, 1 -a] isoquinolin
9 -(3 -Cyclopropy1—propoxy)
((R)—1-[1,4]dioxan
yhnethoxy)-6,7 -dihydropyrimido
[6,1-a]isoquinolin
2-((S)—1-[1,4]Dioxan
ylmethoxy)—9-(3 -meth0xy—
propy1)-6 ,7 -dihydr0 -
pyrimido[6, 1 -a] isoquinolin
2-((S)—1-[1,4]Dioxan
ylmethoxy)-9 -[2-(1 -hydr0xy—
cyclopenty1)-ethy1] -6,7 -
dihydro-pyrimid0[6, 1 -
a]isoquinolin0ne
2-((R)[1,4]Dioxan
ylmethoxy)(4-hydr0xy—
tetrahydro-pyranylethyny1)-
hydr0-pyrimido[6,1-
a]isoquinolin0ne
2-((R)[1,4]Dioxan
ylmethoxy)—9-(3 -meth0xy—
propy1)-6 ,7 -dihydr0 -
do[6, 1 -a] isoquinolin
2-((R)[1,4]Dioxan
ylmethoxy)-9 -[2-(1 -hydr0xy—
cyclopenty1)-ethy1] -6,7 -
dihydro-pyrimid0[6, 1 -
a]isoquinolin0ne
2-((S)—1-[1,4]Dioxan
ylmethoxy)(2-propoxyethoxy
)-6 ,7 -dihydro-
pyrimido[6,1-a]isoquinolin
—1-[1,4]Dioxan
yhnethoxy)(2-isopropoxy—
ethoxy)-6,7 -dihydropyrimido
[6,1-a]isoquinolin
2-((R)[1,4]Dioxan
ylmethoxy)(2-propoxy-
ethoxy)-6 ,7 -dihydropyrimido
[6,1-a]isoquinolin
2-((R)[1,4]Dioxan
yhnethoxy)(2-isopropoxy—
ethoxy)-6 ,7 -dihydropyrimido
]isoquinolin
2-((S)—1-[1,4]Dioxan
ylmethoxy)(4-methoxy—
buty1)-6,7-dihydropyrimido
[6,1-a]isoquinolin
WO 92791
Table III: NMR Data of the Compounds of the Invention
de# NMR data (8)
(1H, CDC13) 6 ppm 7.61 (1 H, d), 6.89 (1 H, dd), 6.78 (1 H, d), 6.26 (1 H, s), 6.13
— 5.94 (1 H, m), 5.48
- 5.24 (2 H, m), 4.59 (2 H, dt), 4.48 - 4.30 (2 H, m), 4.18 (2
H, t), 4.10 - 4.02 (1 H, m), 3.96 (1 H, m), 3.89 — 3.57 (4 H, m), 3.46 (1 H, dd), 2.95
(2 H, t)
(1H, CDC13) 8 ppm 8.89 (1 H, s), 8.67 (1 H, d), 7.93 (1 H, d), 7.82 (1 H, d), 7.61 (1
H, d), 7.53 (1 H, s), 7.43 (1 H, dd), 6.43 (1 H, s), 4.51 - 4.37 (2 H, m), 4.26 (2 H,
t), 3.99 (1 H, m), 3.92 — 3.60 (5 H, m), 3.49 (1 H, m), 3.10 (2 H, t)
(1H, CDC13) 8 ppm 8.77 (2 H, br. s.), 7.86 (1 H, d), 7.76 — 7.46 (4 H, m), 6.48 (1 H,
br. s.), 4.60 — 4.36 (2 H, m), 4.30 (2 H, br. s.), 4.04 (1 H, br. s.), 3.94 — 3.67 (5 H,
m), 3.54 (1 H, t), 3.15 (2 H, br. s.)
(1H, CDC13) 8 ppm 7.83 — 7.53 (4 H,
— 7.94 (2 H, m), 7.78 — 7.71 (1 H, m), 7.67
4 m), 6.48 (1 H, s), 4.53 — 4.43 (2 H, m), 4.34 - 4.27 (2 H, m), 4.07 - 4.01 (1 H, m),
3.93 — 3.67 (5 H, m), 3.54 (1 H, dd), 3.14 (2 H, t)
(1H, CDC13) 8 ppm 7.90 (1 H, d), 7.87- 7.79(2 H, m), 7.73 — 7.69 (1 H, m), 7.65 —
7.56 (2 H, m), 7.52 (1 H, s), 6.45 (1 H, s), 4.51 - 4.37 (2 H, m), 4.27 (2 H, t), 4.06
— 3.95 (1 H, m), 3.91
— 3.61 (5 H, m), 3.51 (1 H, dd), 3.11 (2 H, t)
(1H, CDC13) 8 ppm 7.85 — 7.68 (5 H, m), 7.61 (1 H, dd), 7.54 (1 H, d), 6.44 (1 H,
6 s), 4.51 - 4.36 (2 H, m), 4.26 (2 H, t), 4.00 (1 H, m), 3.91 — 3.61 (5 H, m), 3.50 (1
H, dd), 3.11 (2 H, t)
(1H, CDC13) 8 ppm 7.71 (1 H, d), 7.00 (1 H, dd), 6.90 (1 H, d), 6.31 (1 H, s), 4.86
7 (2 H, s), 4.51 - 4.34 (2 H, m), 4.22 (2 H, t), 3.99 (1 H, m), 3.92 — 3.58 (5 H, m),
3.49 (1 H, dd), 3.03 (2 H, t)
(1H, CDC13) 8 ppm 7.72 (1 H, d), 7.68 — 7.60 (1 H, m), 7.18 (1 H, d), 7.02 (1 H,
dd), 6.93 (1 H, d), 6.28 (1 H, s), 5.23 (2 H, s), 4.49 - 4.33 (2 H, m), 4.19 (2 H, t),
4.02 — 3.94 (1 H, m), 3.89 — 3.61 (5 H, m), 3.48 (1 H, dd), 2.98 (2 H, t)
(H CDC13) 8 ppm 8.63 (1 H, d), 7.75 (1 H, td), 7.64 (1 H, d), 7.50 (1 H, d), 7.29 —
7.24 (1 H, m), 6.99 (1 H, dd), 6.89 (1 H, d), 6.27 (1 H, s), 5.29 (2 H, d), 4.48 —
4.34 (2 H, m), 4.19 (2 H, t), 4.02 — 3.93 (1 H, m), 3.90 — 3.60 (5 H, m), 3.48 (1 H,
dd), 2.97 (2 H, t)
(1H, CDC13) 8 ppm 7.79 (1 H, d), 7.56 (1 H, d), 7.49 (3 H, d), 7.40 (1 H, s), 6.42 (1
H, s), 4.51 - 4.36 (2 H, m), 4.25 (2 H, t), 4.00 (1 H, m), 3.91 — 3.60 (5 H, m), 3.50
(1 H, t), 3.09 (2 H, t)
WO 92791
de# NMR data (8)
(1H, CDC13) 8 ppm 7.87 (1 H, d), 7.83 — 7.76 (2 H, m), 7.64 (1 H, d), 7.56 (1 H, d),
7.41 — 7.32 (1 H, m), 7.31 — 7.23 (3 H, m), 7.18 (1 H, s), 6.43 (1 H, s), 4.46 (2 H,
,_1 ,_1
br. s.), 4.27 (2 H, t), 4.06 — 3.96 (1 H, m), 3.97 — 3.61 (5 H, m), 3.51 (1 H, t), 3.11
(2 H, t)
(1H, CDC13) 8 ppm 8.20 (1 H, d), 7.76 (1 H, d), 7.60 (1 H, d), 7.47 (1 H, dd), 7.42
— 7.35 (2 H, m), 7.336 — 7.26 (1 H, m), 6.68 (1 H, s), 6.44 (1 H, s), 4.54 - 4.40 (2
,_1 [\J
H, m), 4.27 (2 H, t), 4.08 — 3.96 (1 H, m), 3.91 — 3.65 (5 H, m), 3.52 (1 H, dd),
3.08 (2 H, t), 1.42 (9 H, s)
(H DMSO-d6) 8 ppm 8.11 (1 H, d), 7.95 — 7.86 (2 H, m), 7.57 (1 H, d), 7.43 (1 H,
d), 7.15 (1 H, t), 7.10 (1 H, d), 6.71 (1 H, s), 4.31 - 4.25 (2 H, m), 4.09 (2 H, t),
,_1 DJ
3.92 — 3.84 (1 H, m), 3.79 (2 H, td), 3.71 — 3.57 (2 H, m), 3.55 — 3.46 (1 H, m), 3.40
(1 H, dd), 3.08 (2 H, t)
(1H, CDC13) 8 ppm 8.45 (1 H, d), 7.84 (1 H, dd), 7.79 (1 H, d), 7.56 (1 H, dd), 7.50
,_1 4; — 7.46 (1 H, m), 6.87 (1 H, d), 6.43 (1 H, s), 4.49 — 4.36 (2 H, m), 4.30 - 4.19 (2 H,
m), 4.04 — 3.98 (4 H, m), 3.93 — 3.62 (5 H, m), 3.51 (1 H, dd), 3.10 (2 H, t)
(1H, CDC13) 8 ppm 8.97 (1 H, d), 8.09 (1 H, dd), 7.83 (2 H, dd), 7.63 (1 H, dd),
7.55 (1 H, s), 6.44 (1 H, s), 4.52 — 4.36 (2 H, m), 4.27 (2 H, t), 3.99 (1 H, tt), 3.91 -
3.59 (5 H, m), 3.49 (1 H, dd), 3.13 (2 H, t)
(1H, CDC13) 8 ppm 7.73 (1 H, d), 7.57 — 7.50 (2 H, m), 7.48 — 7.45 (1 H, m), 7.42
,_1 (1 H, d), 6.42 (1 H, s), 4.53 - 4.39 (2 H, m), 4.28 — 4.23 (2 H, m), 4.07 — 3.97 (1 H,
m), 3.94 — 3.64 (8 H, m), 3.52 (1 H, dd), 3.06 (2 H, t)
(1H, CDC13) 8 ppm 7.66 (1 H, d), 7.03 (1 H, dd), 6.94 (1 H, d), 6.29 (1 H, s), 5.22
(2 H, s), 4.50 - 4.33 (2 H, m), 4.27 — 4.14 (2 H, m), 4.03 — 3.93 (1 H, m), 3.90 —
3.61 (5 H, m), 3.49 (1 H, dd), 2.99 (2 H, t), 1.47 (9 H, s)
(1H, CDC13) 8 ppm 8.80 (1 H, d), 8.32 (1 H, d), 8.16 — 7.96 (2 H, m), 7.85 (1 H, d),
,_1 7.65 (1 H, dd), 7.57 (1 H, s), 6.45 (1 H, s), 4.56 — 4.37 (2 H, m), 4.28 (2 H, t), 4.01
(1 H, qd), 3.93 — 3.60 (5 H, m), 3.58 — 3.44 (1 H, m), 3.20 — 3.02 (5 H, m)
(1H, CDC13) 8 ppm 7.65 (1 H, d), 7.41 (1 H, dd), 7.36 (1 H, s), 6.38 (1 H, s), 4.50 —
,_1 4.40 (2 H, m), 4.28 _ 4.18 (2 H, m), 4.01 (1 H, m), 3.92 — 3.66 (5 H, m), 3.52 (1 H,
dd), 3.01 (2 H, t), 2.45 (2 H, t), 1.68 (2 H, sxt), 1.09 (3 H, t)
(1H, CDC13) 8 ppm 8.58 (1 H, dd), 7.66 — 7.56 (2 H, m), 7.22 (1 H, dd), 7.19 — 7.09
[\JO (3 H, m), 6.36 (1 H, s), 4.50 — 4.36 (2 H, m), 4.25 — 4.17 (2 H, m), 4.04 - 3.95 (1 H,
m), 3.91 — 3.62 (5 H, m), 3.50 (1 H, dd), 3.14 (4 H, s), 2.98 (2 H, t)
WO 92791
de# NMR data (8)
(1H, CDC13) 8 ppm 8.55 (1 H, dd), 8.44 (2 H, dd), 7.63 (1 H, d), 7.22 (1 H, dd),
[\J ,_1 7.15 (1 H, s), 6.36 (1 H, s), 4.53 — 3.95
— 4.36 (2 H, m), 4.26 — 4.17 (2 H, m), 4.07
(1 H, m), 3.93 — 3.61 (5 H, m), 3.51 (1 H, dd), 3.17 (4 H, s), 2.99 (2 H, t)
(1H, CDC13) 8 ppm 8.51 (1 H, br. s.), 7.94 (1 H, s), 7.79 — 7.67 (2 H, m), 7.61 (1 H,
s), 7.58 — 7.47 (2 H, m), 7.33 (1 H, t), 6.67 (1 H, br. s.), 6.43 (1 H, s), 4.56 — 4.40
(2 H, m), 4.29 (2 H, t), 4.04 (1 H, td), 3.97 — 3.65 (5 H, m), 3.61 — 3.48 (1 H, m),
3.11 (2 H, t)
(1H, CDC13) 8 ppm 7.76 (1 H, d), 7.58 (1 H, d), 7.50 (1 H, s), 7.45 — 7.32 (2 H, m),
DJ 7.13 — 7.01 (2 H, m), 6.43 (1 H, s), 4.45 (2 H, m), 4.27 (2 H, t), 4.01 (1 H, m), 3.94
— 3.63 (8 H, m), 3.52 (1 H, t), 3.08 (2 H, t)
(1H, CDC13) 6 ppm 8.56 - 8.45 (1 H, m), 8.38 (1 H, d), 7.83 (1 H, d), 7.63 (1 H,
N4; dd), 7.54 (1 H, s), 7.42 (1 H, t), 6.45 (1 H, s), 4.54 - 4.36 (2 H, m), 4.31 - 4.23 (2
H, m), 4.05 — 3.96 (4 H, m), 3.93 — 3.62 (5 H, m), 3.52 (1 H, dd), 3.13 (2 H, t)
(1H, CDC13) 8 ppm 8.17 (1 H, d), 8.01 (1 H, s), 7.78 (1 H, d), 7.72 — 7.60 (3 H, m),
[\J LII 7.57 (1 H, d), 6.42 (1 H, s), 4.52 - 4.38 (2 H, m), 4.32 - 4.24 (2 H, m), 4.01 (1 H,
qd), 3.93 — 3.62 (5 H, m), 3.51 (1 H, dd), 3.10 (2 H, t)
(1H, CDC13) 8 ppm 7.74 (1 H, d), 7.57 (3 H, d), 7.48 (1 H, s), 7.01 (2 H, d), 6.40 (1
H, s), 4.51 - 4.36 (2 H, m), 4.25 (2 H, t), 3.99 (1 H, dd), 3.92 — 3.60 (8 H, m), 3.50
(1 H, t), 3.06 (2 H, t)
(1H, CDC13) 8 ppm 8.18 (1 H, s), 7.84 (3 H, d), 7.68 (1 H, dd), 7.64 — 7.55 (2 H,
[\J \1 m), 6.47 (1 H, s), 4.57 — 3.98 (1 H, m), 3.96
— 4.39 (2 H, m), 4.30 (2 H, t), 4.09 —
3.64 (5 H, m), 3.54 (1 H, dd), 3.13 (2 H, t)
(1H, CDC13) 8 ppm 8.45 (1 H, dd), 7.88 — 7.74 (2 H, m), 7.65 (1 H, d), 7.58 (1 H,
00 s), 7.36 — 7.25 (1 H, m), 6.46 (1 H, s), 4.57 — 4.40 (2 H, m), 4.29 (2 H, t), 4.03 (1
H, td), 3.96 — 3.64 (5 H, m), 3.60 — 3.46 (1 H, m), 3.12 (2 H, t)
(H, CDC13) 8ppm 7.99 (1 H, s), 7.80 (1 H, d), 7.64 (1 H, d), 7.56 (1 H, s), 7.50 —
7.32 (3 H, m), 6.45 (1 H, s), 4.56 — 3.97 (1 H,
- 4.40 (2 H, m), 4.29 (2 H, t), 4.11
m), 3.95 — 3.64 (5 H, m), 3.60 — 3.46 (1 H, m), 3.11 (2 H, t), 2.26 (5 H, s)
(1H, CDC13) 8 ppm 7.63 (1 H, d), 7.39 (1 H, dd), 7.33 (1 H, s), 6.41 — 6.34 (1 H,
0 m), 4.53 - 4.39 (2 H, m), 4.29 — 4.18 (1 H, m), 4.06 — 3.97 (1 H, m), 3.93 — 3.64 (5
H, m), 3.52 (1 H, dd), 3.00 (2 H, t), 1.56 — 0.83 (4 H, m)
— 1.45 (1 H, m), 1.01
(1H, CDC13) 8 ppm 7.67 (1 H, d), 7.45 (1 H, dd), 7.39 (1 H, s), 6.40 (1 H, s), 4.53 —
DJ ,_1 4.38 (2 H, m), 4.31 - 4.17(2 H, m), 4.02 (1 H, dd), 3.94 — 3.64 (5 H, m), 3.52 (1 H,
dd), 3.08 — 2.96 (2 H, m), 2.18 — 1.75 (7 H, m), 1.29 (1 H, 5)
de# NMR data (8)
(1H, CDC13) 6 ppm 9.32 (1 H, s), 9.04 (2 H, s), 7.90 (1 H, d), 7.66 (1 H, dd), 7.58
[\J (1 H, s), 6.48 (1 H, s), 4.56 — 3.99 (1 H,
- 4.40 (2 H, m), 4.37 - 4.27 (2 H, m), 4.11
m), 3.96 — 3.64 (5 H, m), 3.60 — 3.46 (1 H, m), 3.17 (2 H, t)
(H, CDC13) 8 ppm 7.67 (1 H, d), 7.42 (1 H, d), 7.32 (1 H, s), 6.39 (1 H, s), 6.31 (1
H, t), 4.54 - 4.38 (2 H, m), 4.25 (2 H, t), 4.02 (1 H, dd), 3.94 — 3.64 (5 H, m), 3.53
(1 H, t), 3.03 (2 H, t), 2.45 (2 H, d), 2.29 (2 H, dd), 1.91 - 1.58 (4 H, m)
(1H, 6) 8 ppm 8.07 (1 H, d), 7.97 (1 H, s), 7.78 — 7.72 (2 H, m), 7.62 —
7.53 (2 H, m), 7.39 (1 H, d), 6.68 (1 H, s), 6.52 (1 H, d), 4.33 — 4.24 (2 H, m), 4.09
(2 H, t), 3.91 — 3.76 (5 H, m), 3.71 — 3.58 (2 H, m), 3.55 — 3.47 (1 H, m), 3.40 (1 H,
m), 3.29 (1 H, s), 3.10 (2 H, t)
(1H, CDC13) 6 ppm 8.84 (1 H, d), 7.96 (1 H, d), 7.85 (1 H, d), 7.64 (1 H, dd), 7.56
DJ LII (1 H, s), 7.40 (1 H, d), 6.47 (1 H, s), 4.55 - 4.40 (2 H, m), 4.37 - 4.23 (2 H, m),
4.04 (1 H, m), 3.95 — 3.65 (5 H, m), 3.54 (1 H, dd), 3.14 (2 H, t), 2.74 (3 H, 5)
(1H, CDC13) 8 ppm 8.69 (1 H, d), 7.78 — 7.72 (2 H, m), 7.65 — 7.57 (3 H, m), 7.33
DJ 0\
(1 H, m), 6.43 (1 H, s), 4.54 - 4.39 (2 H, m), 4.27 (2 H, t), 4.05 (1 H, s), 3.95 —
3.64 (5 H, m), 3.53 (1 H, dd), 3.07 (2 H, t)
(1H, CDC13) 8 ppm 7.68 (1 H, d), 7.47 (1 H, dd), 7.42 (1 H, s), 6.40 (1 H, s), 4.53 —
4.41 (2 H, m), 4.38 (2 H, s), 4.24 (2 H, t), 4.07 — 3.96 (1 H, m), 3.93 — 3.63 (5 H,
m), 3.55 — 3.33 (4 H, m), 3.03 (2 H, t)
(1H, CDC13) 8 ppm 7.67 (1 H, d), 7.44 (1 H, dd), 7.39 (1 H, s), 6.39 (1 H, s), 4.50 —
DJ 00 4.40 (2 H, m), 4.26 - 4.20 (2 H, m), 4.04 — 3.98 (1 H, m), 3.91 — 3.65 (5 H, m), 3.52
(1 H, dd), 3.02 (2 H, t), 2.90 — 2.83 (2 H, m), 2.75 - 2.68 (2 H, m)
(H CDC13) 8 ppm 7.64 (1 H, d), 7.42 (1 H, dd), 7.37 (1 H, s), 6.38 (1 H, s), 4.51
(2 H, s), 4.48 - 4.378 (2 H, m), 4.19 (2 H, t), 4.03 — 3.96 (1 H, m), 3.89 — 3.64 (5 H,
m), 3.51 (1 H, dd), 2.99 (2 H, t)
(1H, CDC13) 8 ppm 7.65 (1 H, d), 7.50 — 7.44 (3 H, m), 7.41 (1 H, s), 6.94 — 6.84 (2
H, m), 6.35 (1 H, s), 4.45 - 4.36 (2 H, m), 4.19 (2 H, t), 4.04 — 3.91 (1 H, m), 3.87 —
4;0 3.62 (8 H, m), 3.48 (1 H, dd),7.81 (1 H, d), 7.59 — 7.48 (2 H, m), 7.43 (1 H, s),
7.41 — 7.33 (3 H, m), 6.47 (1 H, s), 4.54 - 4.42 (2 H, m), 4.30 (2 H, t), 4.03 (1 H,
dt), 3.95 — 3.65 (5 H, m), 3.54 (1 H, dd), 3.11 (2 H, t)
(1H, CDC13) 8 ppm 8.78 (1 H, d), 8.59 (1 H, dd), 7.83 (1 H, dt), 7.71 (1 H, d), 7.54
(1 H, dd), 7.49 (1 H, s), 7.39 — 7.25 (1 H, m), 6.40 (1 H, s), 4.51 - 4.33 (2 H, m),
4.30 — 3.93 (1 H, m), 3.90
— 4.16 (2 H, m), 4.07 — 3.59 (5 H, m), 3.49 (1 H, dd),
3MQH0
WO 92791
de# NMR data (8)
(1H, CDC13) 5 ppm 7.93 (2 H, d), 7.78 (1 H, d), 7.72 — 7.59 (3 H, m), 7.54 (1 H, s),
4;N 6.42 (1 H, s), 4.49 - 4.35(2 H, m), 4.23 (2 H, t), 4.05 — 3.95 (1 H, m), 3.91 — 3.61 (5
H, m), 3.49 (1 H, t), 3.16 — 2.97 (5 H, m)
(H, CDC13) 6 ppm 7.81 (1 H, d), 7.64 (1 H, d), 7.55 (1 H, br. s.), 7.50 - 7.37 (1 H,
m), 7.24 (1 H, d), 7.18 (1 H, br. s.), 7.00 (1 H, d), 6.46 (1 H, br. s.), 4.47 (2 H, d),
4.30 (2 H, br. s.), 4.04 (1 H, br. s.), 3.98 - 3.66 (7 H, m), 3.54 (1 H, t), 3.12 (2 H,
br. s.), 1.83 (1 H, br. s.)
(1H, CDC13) 5 ppm 7.81 (1 H, d), 7.59 — 7.48 (2 H, m), 7.43 (1 H, s), 7.41 — 7.33 (3
H, m), 6.47 (1 H, s), 4.54 - 4.42 (2 H, m), 4.30 (2 H, t), 4.03 (1 H, dt), 3.95 — 3.65
(5 H, m), 3.54 (1 H, dd), 3.11 (2 H, t)
(1H, CDC13) 5 ppm 7.62 (1 H, d), 7.39 (1 H, d), 7.34 (1 H, s), 6.36 (1 H, s), 4.51 —
4; U) 4.34 (2 H, m), 4.19 (2 H, t), 3.99 (1 H, td), 3.91 — 3.59 (7 H, m), 3.50 (1 H, dd),
2.98 (2 H, t), 2.74 (2 H, t)
(H CDC13) 5 ppm 7.64 (1 H, d), 7.02 (1 H, dd), 6.92 (1 H, d), 6.30 (1 H, s), 6.13
4; 0\ (1 H, s), 5.09 (2 H, s), 4.51 — 4.36 (2 H, m), 4.22 (2 H, t), 4.07 - 3.97 (1 H, m),
3.92 — 3.61 (8 H, m), 3.57 — 3.44 (1 H, m), 2.99 (2 H, t), 2.30 (3 H, s)
(1H, CDC13) 5ppm 7.62 (1 H, d), 7.37 (1 H, d), 7.00 (1 H, dd), 6.90 (1 H, d), 6.33
(1 H, d), 6.27 (1 H, s), 5.12 (2 H, s), 4.47 - 4.34 (2 H, m), 4.23 - 4.143 (2 H, m),
4.02 — 3.89 (4 H, m), 3.88 — 3.59 (5 H, m), 3.48 (1 H, dd), 2.96 (2 H, t)
(1H, CDC13) 5 ppm 7.67 (1 H, d), 6.99 (1 H, dd), 6.90 (1 H, d), 6.29 (1 H, s), 5.33
4; 00 (2 H, s), 4.47 - 4.35 (2 H, m), 4.20 (2 H, t), 4.03 — 3.93 (1 H, m), 3.89 — 3.60 (5 H,
m), 3.48 (1 H, dd), 2.99 (2 H, t), 2.45 (3 H, s)
(H CDC13) 5 ppm 7.77 (1 H, d), 7.66 — 7.57 (3 H, m), 7.52 (1 H, d), 7.04 (2 H, d),
6 6.43 (1 H, s), 4.55 - 4.40 (2 H, m), 4.35 — 4.24 (2 H, m), 4.04 (1 H, dd), 3.97 — 3.66
(9 H, m), 3.54 (1 H, dd), 3.32 — 3.20 (4 H, m), 3.10 (2 H, s)
(1H, CDC13) 5 ppm 8.06 (1 H, dd), 7.92 — 7.78 (2 H, m), 7.63 (1 H, d), 7.56 (1 H,
s), 7.36 — 7.24 (1 H, m), 6.47 (1 H, s), 4.55 - 4.38 (2 H, m), 4.28 (2 H, t), 4.13 -
3.99 (1 H, m), 3.95 — 3.65 (5 H, m), 3.54 (1 H, t), 3.11 (2 H, t)
(1H, CDC13) 5 ppm 7.95 (1 H, t), 7.80 (1 H, d), 7.67 — 7.54 (3 H, m), 7.54 — 7.45 (1
,_1 H, m), 6.44 (1 H, s), 4.52 - 4.35 (2 H, m), 4.31 - 4.19 (2 H, m), 4.09 — 3.96 (1 H,
m), 3.95 — 3.64 (5 H, m), 3.58 — 3.46 (1 H, m), 3.10 (2 H, t)
(1H, CDC13) 5 ppm 7.64 (1 H, d), 7.40 (1 H, dd), 7.35 (1 H, d), 6.38 (1 H, s), 4.52 —
LI] [\J 4.39 (2 H, m), 4.26 - 4.16 (2 H, m), 4.04 — 3.96 (1 H, m), 3.93 — 3.63 (5 H, m), 3.51
(1 H, dd), 3.00 (2 H, t), 1.36 (9 H, 5)
WO 92791
de# NMR data (8)
(1H, CDC13) 5 ppm 8.72 — 8.64 (2 H, m), 7.75 (1 H, d), 7.59 (1 H, dd), 7.54 (1 H,
s), 7.48 — 7.42 (2 H, m), 6.44 (1 H, s), 4.55 - 4.39 (2 H, m), 4.34 - 4.22 (2 H, m),
4.03 (1 H, dd), 3.95 — 3.64 (5 H, m), 3.53 (1 H, dd), 3.08 (2 H, t)
(1H, CDC13) 5 ppm 7.68 (1 H, d), 6.98 (1 H, dd), 6.89 (1 H, d), 6.31 (1 H, s), 6.23
(1 H, s), 5.22 (2 H, s), 4.52 - 4.36 (2 H, m), 4.29 - 4.18 (2 H, m), 4.07 — 3.96 (1 H,
m), 3.93 — 3.63 (5 H, m), 3.51 (1 H, dd), 3.06 — 2.96 (2 H, m), 2.35 (3 H, s)
(1H, CDC13) 5 ppm 7.60 (1 H, d), 7.39 — 7.35 (1 H, m), 7.32 (1 H, d), 6.33 (1 H, s),
LII LII 4.45 - 4.35 (2 H, m), 4.17 (2 H, t), 3.97 (1 H, m), 3.87 — 3.60 (5 H, m), 3.47 (1 H,
dd), 2.95 (2 H, t), 1.62 (6 H, s)
(1H, CDC13) 5 ppm 8.24 (1 H, dd), 7.78 (1 H, d), 7.67 (1 H, dd), 7.61 (1 H, dd),
LII 0\ 7.54 (1 H, s), 7.04 (1 H, dd), 6.45 (1 H, s), 4.52 - 4.41 (2 H, m), 4.28 (2 H, t), 4.02
(4 H, s), 3.93 — 3.64 (5 H, m), 3.52 (1 H, dd), 3.10 (2 H, t)
(1H, CDC13) 5 ppm 7.70 (1 H, d), 7.43 (1 H, dd), 7.33 (1 H, d), 6.39 (1 H, s), 6.31
LII 00 (1 H, dt), 4.53 - 4.34 (4 H, m), 4.31 - 4.19 (2 H, m), 4.06 — 3.94 (3 H, m), 3.92 —
3.61 (5 H, m), 3.51 (1 H, dd), 3.04 (2 H, t), 2.62 - 2.50 (2 H, m)
(H, CDC13) 5 ppm 9.02 (1 H, d), 8.09 (1 H, dd), 7.97 — 7.80 (2 H, m), 7.67 (1 H,
dd), 7.59 (1 H, d), 6.48 (1 H, s), 4.56 — 4.38 (2 H, m), 4.36 - 4.25 (2 H, m), 4.03 (1
H, m), 3.95 — 3.63 (5 H, m), 3.53 (1 H, dd), 3.16 (2 H, t)
(1H, CDC13) 5 ppm 8.43 (1 H, d), 7.86 — 7.74 (2 H, m), 7.56 (1 H, dd), 7.47 (1 H,
d), 6.80 (1 H, d), 6.43 (1 H, s), 5.44 — 5.31 (1 H, m), 4.53 - 4.37 (2 H, m), 4.26 (2
H, t), 4.01 (1 H, m), 3.92 - 3.62 (5 H, m), 3.51 (1 H, dd), 3.09 (2 H, t), 1.40 (6 H,
(1H, CDC13) 5 ppm 8.44 (1 H, d), 7.84 (1 H, dd), 7.79 (1 H, d), 7.57 (1 H, dd), 7.48
,_1 (1 H, d), 6.85 (1 H, d), 6.43 (1 H, s), 4.54 - 4.37 (4 H, m), 4.27 (2 H, t), 4.02 (1 H,
m), 3.93 — 3.62 (5 H, m), 3.52 (1 H, dd), 3.10 (2 H, t), 1.45 (3 H, t)
(1H, CDC13) 5 ppm 8.52 (1 H, d), 7.85 — 7.72 (2 H, m), 7.56 (1 H, dd), 7.47 (1 H,
d), 6.75 (1 H, d), 6.42 (1 H, s), 4.52 — 4.38 (2 H, m), 4.32 - 4.22 (2 H, m), 4.06 -
3.97 (1 H, m), 3.93 — 3.58 (13 H, m), 3.52 (1 H, dd), 3.09 (2 H, s)
(1H, CDC13) 5 ppm 7.77 (1 H, d), 7.60 (1 H, dd), 7.52 (1 H, d), 7.21 - 7.12 (1 H,
O\ m), 6.99 (2 H, ddd), 6.45 (1 H, s), 4.53 — 4.40 (2 H, m), 4.28 (2 H, t), 4.06 — 3.98 (1
H, m), 3.95 (3 H, s), 3.92 — 3.63 (8 H, m), 3.52 (1 H, dd), 3.08 (2 H, t)
(H, CDC13) 5 ppm 8.15 (1 H, d), 7.82 (1 H, d), 7.50 (1 H, dd), 7.45 — 7.40 (1 H,
O\4; m), 6.91 (1 H, d), 6.46 (1 H, s), 4.54 - 4.40 (2 H, m), 4.29 (2 H, t), 4.11 (2 H, s),
4.07 — 3.98 (1 H, m), 3.94 — 3.64 (4 H, m), 3.53 (1 H, dd), 3.11 (2 H, t)
WO 92791
de# NMR data (8)
(1H, CDC13) 8 ppm 8.62 (1 H, d), 7.84 (1 H, d), 7.67 (1 H, dd), 7.59 (1 H, d), 7.42
(1 H, s), 7.36 (1 H, dd), 6.46 (1 H, s), 4.54 - 4.38 (2 H, m), 4.33 - 4.24 (2 H, m),
4.07 — 3.97 (1 H, m), 3.94 — 3.63 (5 H, m), 3.52 (1 H, dd), 3.13 (2 H, t), 2.68 (3 H,
(H, CDC13) 8 ppm 8.88 (1 H, s), 8.82 (1 H, d), 7.88 (1 H, d), 7.68 (1 H, dd), 7.61
(1 H, dd), 7.53 (1 H, s), 6.45 (1 H, s), 4.49 - 4.38 (2 H, m), 4.27 (2 H, t), 4.00 (1 H,
ddt), 3.90 — 3.61 (5 H, m), 3.49 (1 H, dd), 3.13 (2 H, t)
(1H, CDC13) 8 ppm 7.76 (1 H, d), 7.58 (1 H, dd), 7.50 (1 H, s), 6.88 — 7.03 (3 H,
\1 m), 6.44 (1 H, s), 4.54 - 4.39 (2 H, m), 4.28 (2 H, t), 4.03 (1 H, m), 3.95 — 3.63 (11
H, m), 3.53 (1 H, dd), 3.08 (2 H, t)
(1H, CDC13) 8 ppm 8.50 (1 H, d), 7.74 (2 H, td), 7.55 (1 H, dd), 7.45 (1 H, s), 6.75
(1 H, d), 6.40 (1 H, s), 4.56 - 4.38 (2 H, m), 4.26 (2 H, t), 4.01 (1 H, m), 3.94 -
3.58 (9 H, m), 3.52 (1 H, dd), 3.08 (2 H, t), 1.70 (6 H, br. s.)
(1H, CDC13) 8 ppm 8.21 (1 H, dd), 7.78 (1 H, d), 7.66 (2 H, ddd), 7.56 (1 H, s),
7.01 (1 H, dd), 6.45 (1 H, s), 4.54 - 4.39 (4 H, m), 4.28 (2 H, t), 4.03 (1 H, m),
3.94 — 3.64 (5 H, m), 3.53 (1 H, dd), 3.09 (2 H, t), 1.42 (3 H, t)
(1H, CDC13) 8 ppm 7.75 (1 H, d), 7.64 (1 H, d), 7.60 (1 H, dd), 7.52 (1 H, d), 6.47
(1 H, d), 6.43 (1 H, s), 4.53 — 4.39 (2 H, m), 4.33 — 4.23 (2 H, m), 4.03 (6 H, d),
3.94 — 3.64 (5 H, m), 3.59 — 3.48 (2 H, m), 3.08 (2 H, t)
(1H, CDC13) 8 ppm 9.00 (1 H, s), 8.87 (1 H, d), 7.87 (1 H, d), 7.63 (1 H, dd), 7.56
\l ,_1 (1 H, s), 7.52 — 7.48 (1 H, m), 6.45 (1 H, s), 4.51 - 4.36 (2 H, m), 4.26 (2 H, t),
3.99 (1 H, ddt), 3.90 — 3.60 (5 H, m), 3.54 - 3.44 (1 H, m), 3.12 (2 H, t)
(1H, CDC13) 8 ppm 7.65 (1 H, d), 7.34 (1 H, d), 7.30 (1 H, s), 6.36 (1 H, s), 4.48 (2
\1 H, s), 4.46 - 4.34 (2 H, m), 4.18 (2 H, t), 4.02 — 3.92 (1 H, m), 3.89 — 3.60 (5 H, m),
3.54 — 3.42 (1 H, m), 3.00 (2 H, t), 1.30 (9 H, s)
(1H, CDC13) 8 ppm 8.19 (1 H, dd), 7.69 (1 H, d), 7.38 (2 H, ddd), 7.29 (1 H, d),
6.72 (1 H, dd), 6.40 (1 H, s), 4.47 — 4.37 (2 H, m), 4.24 (2 H, t), 4.03 - 3.93 (1 H,
m), 3.89 — 3.59 (5 H, m), 3.49 (1 H, t), 3.18 — 3.08 (4 H, m), 3.04 (2 H, t), 1.82 -
1.72 (4 H, m)
(1H, CDC13) 8 ppm 8.51 (1 H, d), 7.75 (2 H, td), 7.56 (1 H, dd), 7.46 (1 H, s), 6.48
(1 H, d), 6.41 (1 H, s), 4.56 - 4.37 (2 H, m), 4.27 (2 H, t), 4.02 (1 H, dd), 3.95 —
3.63 (5 H, m), 3.61 — 3.45 (5 H, m), 3.09 (2 H, t), 2.14 - 1.99 (4 H, m)
(1H, CDC13) 8 ppm 7.70 — 7.57 (2 H, m), 7.47 — 7.20 (5 H, m), 7.05 (1 H, dd), 6.96
\1 LI] (1 H, d), 6.27 (1 H, s), 5.26 (2 H, s), 4.47 - 4.32 (2 H, m), 4.23 - 4.15 (2 H, m),
4.03 — 3.91 (1 H, m), 3.89 — 3.56 (5 H, m), 3.47 (1 H, dd), 2.97 (2 H, t)
de# NMR data (8)
(1H, CDC13) 5 ppm 7.67 (1 H, d), 7.05 (1 H, dd), 6.96 (1 H, d), 6.75 (1 H, s), 6.31
(1 H, s), 5.18 (2 H, s), 4.53 - 4.34 (2 H, m), 4.22 (2 H, t), 4.00 (1 H, m), 3.92 -
3.62 (5 H, m), 3.50 (1 H, dd), 3.00 (2 H, t), 1.32 (9 H, s)
(1H, CDC13) 5 ppm 7.64 (1 H, d), 7.00 (1 H, dd), 6.91 (1 H, d), 6.27 (1 H, s), 5.17
(2 H, s), 4.47 - 4.32 (2 H, m), 4.23 - 4.14 (2 H, m), 3.96 (1 H, qd), 3.89 — 3.58 (5
H, m), 3.47 (1 H, dd), 2.97 (2 H, t), 2.29 - 2.17 (1 H, m), 1.30 4 H, m)
(1H, CDC13) 5 ppm 7.65 (1 H, d), 7.01 (1 H, dd), 6.92 (1 H, d), 6.27 (1 H, s), 5.22
\l 00 (2 H, s), 4.47 - 4.30 (2 H, m), 4.24 — 4.13 (2 H, m), 3.96 (1 H, m), 3.90 — 3.580 (5
H, m), 3.47 (1 H, dd), 3.02 - 2.85 (4 H, m), 1.41 (3 H, t)
(H CDC13) 5 ppm 7.68 (1 H, d), 7.05 (1 H, dd), 6.95 (1 H, d), 6.32 (1 H, s), 5.26
\l \0 (2 H, s), 4.52- 4.37 (2 H, m), 4.28 - 4.20 (2 H, m), 4.06 — 3.96 (1 H, m), 3.94 — 3.62
(5 H, m), 3.51 (1 H, dd), 3.02 (2 H, t), 2.67 (3 H, s)
(1H, CDC13) 5 ppm 7.65 (1 H, d), 7.02 (1 H, dd), 6.93 (1 H, d), 6.28 (1 H, s), 5.22
(2 H, s), 4.47 - 4.33 (2 H, m), 4.19 (2 H, t), 4.03 — 3.91 (1 H, m), 3.89 — 3.59 (5 H,
m), 3.48 (1 H, dd), 3.26 (1 H, dt), 2.99 (2 H, t), 1.43 (6 H, d)
(1H, CDC13) 5 ppm 7.63 (1 H, d), 7.40 (1 H, dd), 7.34 (1 H, s), 6.38 (1 H, s), 4.53 —
4.37 (2 H, m), 4.27 - 4.17 (2 H, m), 4.05 — 3.96 (1 H, m), 3.93 — 3.63 (5 H, m), 3.58
— 1.97 (2 H, m), 1.90
- 3.46 (1 H, m), 3.00 (2 H, t), 2.88 (1 H, m), 2.13 — 1.56 (6 H,
(1H, CDC13) 5 ppm 7.64 (1 H, d), 7.41 (1 H, d), 7.35 (1 H, s), 6.38 (1 H, s), 4.52 —
00 [\J 4.36 (2 H, m), 4.22 (2 H, t), 4.01 (1 H, m), 3.93 — 3.63 (5 H, m), 3.51 (1 H, t), 3.00
(2 H, t), 2.71 - 2.58 (1 H, m), 1.99 - 1.31 (10 H, m)
(H CDC13) 5 ppm 7.64 (1 H, d), 7.40 (1 H, dd), 7.35 (1 H, s), 6.38 (1 H, s), 4.49 —
00 DJ 4.40 (2 H, m), 4.22 (2 H, t), 4.05 - 3.97 (1 H, m), 3.91 — 3.65 (5 H, m), 3.51 (1 H,
dd), 3.00 (2 H, t), 2.88 — 2.78 (1 H, m), 1.31 (6 H, d)
(1H, CDC13) 5 ppm 7.64 (1 H, d), 7.40 (1 H, dd), 7.35 (1 H, s), 6.38 (1 H, s), 4.51 —
4.38 (2 H, m), 4.26 - 4.18 (2 H, m), 4.07 — 3.97 (1 H, m), 3.93 — 3.64 (5 H, m), 3.52
(1 H, dd), 3.00 (2 H, t), 2.47 (2 H, t), 1.70 — 1.45 (4 H, m), 0.99 (3 H, t)
(1H, CDC13) 5 ppm 7.65 (1 H, d), 7.45 (1 H, dd), 7.41 — 7.31 (5 H, m), 7.27 (1 H,
s), 6.37 (1 H, s), 4.49 — 4.34 (2 H, m), 4.24 - 4.17 (2 H, m), 4.02 - 3.94 (1 H, m),
3.90 — 3.60 (7 H, m), 3.54 (2 H, s), 3.52 — 3.45 (1 H, m), 3.00 (2 H, t), 2.42 (3 H, s)
(1H, CDC13) 5 ppm 7.63 (1 H, d), 7.42 (1 H, dd), 7.36 (1 H, s), 6.37 (1 H, s), 4.70 —
4.65 (1 H, m), 4.47 - 4.37 (2 H, m), 4.20 (2 H, t), 400—397 (1 H, m), 3.88 — 3.63
(5 H, m), 3.49 (1 H, t), 2.99 (2 H, t), 1.93 — 0.97 (6 H, m)
— 1.65 (4 H, m), 1.00
de# NMR data (8)
(1H, CDC13) 8 ppm 7.63 (1 H, d), 7.42 (1 H, d), 7.36 (1 H, s), 6.37 (1 H, s), 4.80 —
4.77 (1 H, m), 4.46 - 4.37 (2 H, m), 4.20 (2 H, t), 401—397 (1 H, m), 3.89 — 3.65
(5 H, m), 3.49 (1 H, t), 2.99 (2 H, t), 1.99 (1 H, d), 1.57 (3 H, d)
(1H, CDC13) 8 ppm 7.60 (1 H, d), 7.07 (1 H, d), 6.99 (1 H, s), 6.35 (1 H, s), 4.49 —
4.38 (2 H, m), 4.21 (2 H, t), 4.01 (1 H, m), 3.94 - 3.62 (5 H, m), 3.51 (1 H, t), 2.99
(2 H, t), 2.07 - 1.86 (1 H, m), 1.15 — 1.06 (2 H, m), 0.85 — 0.78 (2 H, m)
(1H, DMSO-d6) 8 ppm 8.00 (1 H, d), 7.46 (1 H, s), 7.40 (1 H, d), 6.68 (1 H, s),
.53 (1 H, d), 4.43 - 4.41 (1 H, m), 4.26 - 4.25 (2 H, m), 4.01 (2 H, t), 3.87 — 3.40
(7 H, m), 3.00 (2 H, t), 1.67 — 1.65 (2 H, m), 0.98 (3 H, t)
(1H, 6) 8 ppm 8.00 (1 H, d), 7.46 (1 H, s), 7.40 (1 H, d), 6.68 (1 H, s),
.53 (1 H, d), 4.28 — 4.25 (3 H, m), 4.01 (2 H, t), 3.85 — 3.38 (7 H, m), 3.00 (2 H,
t), 1.85 — 1.80 (1 H, m), 0.98 (6 H, t)
(1H, DMSO-d6) 8 ppm 8.00 (1 H, d), 7.44 (1 H, s), 7.38 (1 H, d), 6.68 (1 H, s),
.27 (1 H, S), 4.26 - 4.25 (2 H, m), 4.01 (2 H, t), 3.86 — 3.74 (3 H, m), 3.67 — 3.60
(2 H, m) 3.52 — 3.46 (1 H, m), 3.37 — 3.35 (1 H, m), 3.00 (2 H, t), 1.66 — 1.62 (4 H,
m), 0.99 (6 H, t)
(1H, CDC13) 8 ppm 7.71 (2 H, d), 7.66 (1 H, d), 7.47 (1 H, d), 7.43 — 7.32 (4 H, m),
\o [\J 6.38 (1 H, s), 4.47 — 4.37 (2 H, m), 4.20 (2 H, t), 4.00 — 3.98 (1 H, m), 3.97 — 3.68
(5 H, m), 3.49 (1 H, t), 3.00 (2 H, t), 2.53 (1 H, s), 1.88 (3 H, s)
(H, CDC13) 8 ppm 7.64 (1 H, d), 7.43 — 7.29 (7 H, m), 6.37 (1 H, s), 4.46 — 4.37 (2
6 DJ H, m), 4.21 (2 H, t), 3.99 — 3.95 (3 H, m), 3.88 — 3.63 (7 H, m), 3.49 (1 H, t), 2.99
(2 H, t)
(1H, CDC13) 8 ppm 7.57 — 7.48 (1 H, d), 7.38 (1 H, s), 6.68 — 6.55 (1 H, d), 6.49 (1
H, s), 6.35 (1 H, s), 6.28 (1 H, s), 6.20 (1 H, s), 4.60 — 4.50 (1 H, m), 4.38 — 4.30 (4
H, m), 4.22 - 4.15 (2 H, m), 4.03 — 3.93 (1 H, m), 3.95 — 3.60 (5 H, m), 3.55 —3.40
(1 H, t), 2.98 - 2.85 (2 H, m)
(1H, CDC13) 8 ppm 7.86 (1 H, s), 7.77 (1 H, s), 7.70 (1 H, d), 7.51 (1 H, d), 7.42 (1
6 LI] H, s), 6.39 (1 H, s), 4.51 — 4.37 (2 H, m), 4.330 — 4.20 (4 H, m), 4.05 — 3.96 (1 H,
m), 3.87 (5 H, s), 3.51 (1 H, dd), 3.05 (2 H, t), 1.57 (4 H, t)
(1H, CDC13) 8 ppm 7.85 (1 H, s), 7.75 (1 H, s), 7.70 (1 H, d), 7.50 (1 H, dd), 7.42
(1 H, s), 6.39 (1 H, s), 4.50 — 4.39 (2 H, m), 4.27 — 4.18 (4 H, m), 4.05 — 3.97 (1 H,
m), 3.86 (5 H, m), 3.51 (1 H, dd), 3.05 (2 H, t), 1.88 — 1.79 (2 H, m), 1.69 — 1.59 (1
H, m), 1.00 (6 H, d)
WO 92791
de# NMR data (8)
(1H, CDC13) 5 ppm 8.03 (1 H, d), 7.67 — 7.63 (2 H, m), 7.05 (1 H, d), 6.65 (1 H, s),
\o \1 6.28 (1 H, dd), 4.30 — 4.23 (2 H, m), 4.04 (2 H, t), 3.89 — 3.75 (3 H, m), 3.63 (2 H,
dd), 3.50 (1 H, d), 3.39 (1 H, dd), 3.04 (2 H, t), 2.37 (3 H, s)
(1H, CDC13) 5 ppm 7.64 (1 H, d), 7.42 (1 H, d), 7.36 (1 H,s), 6.37 (1 H, s), 4.66 —
4.61 (1 H, m), 4.47 - 4.37 (2 H, t), 4.20 (2 H, t), 4.00 — 3.88 (1 H, m), 3.88 — 3.46
(5 H, m), 3.49 (1 H, t), 2.99 (2 H, t), 1.90 - 1.89 (1 H, m), 1.81 - 1.77 (2 H, m),
1.57 — 1.54 (2 H, m), 1.00 (3 H, t)
(1H, CDC13) 5 ppm 7.75 (1 H, d), 7.33 — 7.28 (1 H, m), 7.22 (1 H, s), 6.41 (1 H, s),
4.50 — 4.39 (2 H, m), 4.29 — 4.23 (2 H, m), 4.05 — 3.97 (1 H, m), 3.85 (5 H, m), 3.54
— 3.47 (1 H, m), 3.07 (2 H, d), 2.36 (6 H, s)
(1H, CDC13) 5 ppm 8.36 (1 H, br. s.), 8.07 (1 H, br. s.), 7.99 (1 H, d), 7.64 — 7.70 (2
H, m), 6.65 (1 H, s), 4.31 - 4.22 (2 H, m), 4.05 (2 H, t), 3.90 — 3.84 (1 H, m), 3.79
(2 H, td), 3.70 — 3.57 (2 H, m), 3.51 — 3.50 (1 H, m), 3.55 — 3.45 (1 H, m), 3.39 (1
H, dd), 3.01 (2 H, t)
(1H, CDC13) 5 ppm 7.85 (1 H, d), 7.74 (1 H, d), 7.70 (1 H, d), 7.50 (1 H, dd), 7.44
— 7.38 (1 H, m), 6.38 (1 H, s), 4.48 — 4.348 (2 H, m), 4.27 - 4.17 (2 H, m), 4.15 (2
H, t), 4.04 — 3.96 (1 H, m), 3.90 — 3.64 (5 H, m), 3.50 (1 H, dd), 3.04 (2 H, t), 2.02
— 1.90 (2 H, m), 0.97 (3 H, t)
(1H, CDC13) 5 ppm 7.91 — 7.80 (2 H, m), 7.71 (1 H, dd), 7.62 — 7.45 (4 H, m), 6.45
(1 H, s), 4.49 - 4.39 (2 H, m), 4.27 (2 H, t), 4.06 — 3.94 (1 H, m), 3.92 — 3.61 (5 H,
m), 3.51 (1 H, dd), 3.11 (2 H, t)
(1H, CDC13) 5 ppm 7.80 — 7.90 (2 H, m), 7.79 — 7.69 (1 H, m), 7.66 — 7.51 (4 H, m),
6.47 (1 H, s), 4.57 - 4.41 (2 H, m), 4.30 (2 H, t), 4.03 (1 H, dt), 3.95 — 3.64 (5 H,
m), 3.53 (1 H, t), 3.14 (2 H, t)
(1H, CDC13) 5 ppm 7.65 (1 H, d), 7.01 (1 H, dd), 6.91 (1 H, d), 6.28 (1 H, s), 5.18
(2 H, s), 4.47 - 4.35 (2 H, m), 4.24 - 4.15 (2 H, m), 4.02 — 3.93 (1 H, m), 3.89 —
3.61 (5 H, m), 3.48 (1 H, dd), 2.98 (2 H, t), 2.29 - 2.18 (1 H, m), 1.33 - 1.20 (4 H,
(1H, CDC13) 5 ppm 7.65 (1 H, s), 7.51 — 7.46 (1 H, m), 7.45 — 7.41 (1 H, m), 6.37
(1 H, s), 4.49 - 4.36 (2 H, m), 4.21 (2 H, s), 4.04 — 3.94 (1 H, m), 3.90 — 3.610 (5
H, m), 3.53 — 3.44 (1 H, m), 3.25 (1 H, s), 3.00 (2 H, s)
(1H, CDC13) 5 ppm 9.18 (1 H, s), 8.88 (2 H, s), 7.72 (1 H, d), 7.60 — 7.53 (1 H, m),
7.51 (1 H, d), 6.40 (1 H, s), 4.49 — 4.36 (2 H, m), 4.23 (2 H, t), 4.02 - 3.95 (1 H,
m), 3.89 — 3.58 (5 H, m), 3.49 (1 H, dd), 3.04 (2 H, t)
2012/076275
de# NMR data (8)
(1H, CDC13) 5 ppm: 7.54 (1 H, d), 7.37 (1 H, dd), 7.32 (1 H,s), 7.26 — 7.22 (2 H,
107 m), 6.81 (1 H, t), 6.75 (2 H, dd), 6.35 (1 H, s), 4.46 — 4.36 (2 H, m), 4.20 - 4.17 (4
H, m), 4.00 — 3.91 (1 H, m), 3.88 — 3.63 (5 H, m), 3.49 (1 H, t), 2.97 (2 H, t)
(1H, CDC13) 5 ppm 8.36 (1 H, d), 7.89 — 7.65 (3 H, m), 7.62 — 7.55 (3 H, m), 6.44
(1 H, s), 4.51 - 4.38 (2 H, m), 4.26 (2 H, t), 4.00 (1 H, m), 3.91 — 3.62 (5 H, m),
3.50 (1 H, dd), 3.22 — 3.14 (1 H, m), 3.09 (2 H, t), 1.40 (1 H, t)
(1H, CDC13) 5 ppm 7.70 — 7.60 (1 H, d), 7.50 — 7.42 (1 H, d), 7.39 (1 H, s), 6.37 (1
H, s), 4.50 - 4.35 (2 H, m), 4.25 — 4.15 (2 H, m), 4.05 — 3.95 (2 H, m), 3.92 — 3.60
(5 H, m), 3.56 — 3.45 (4 H, m), 3.05 — 3.95 (2 H, m), 2.15 - 1.95 (1 H, m), 1.15 -1
(6 HA)
(1H, CDC13) 5 ppm 7.58 (1 H, d), 7.33 (1 H, d), 7.27 (1 H, s), 6.32 (1 H, s), 4.45 —
4.34 (2 H, m), 4.17 (2 H, t), 3.96 (1 H, qd), 3.86 — 3.60 (5 H, m), 3.46 (1 H, dd),
2.94 (2 H, t), 1.46 (1 H, tt), 0.94 — 0.86 (2 H, m), 0.86 — 0.79 (2 H, m)
(1H, CDC13) 5 ppm 7.61 (1 H, d), 7.22 (1 H, d), 7.14 (1 H, s), 6.34 (1 H, s), 4.48 -
4.34 (2 H, m), 4.19 (2 H, t), 4.02 - 3.93 (1 H, m), 3.89 — 3.60 (5 H, m), 3.48 (1 H,
t), 3.43 — 3.35 (1 H, m), 2.98 (2 H, t), 2.95 - 2.85 (1 H, m), 2.76 - 2.64 (1 H, m),
1.84 - 1.62 (3 H, m), 0.92 (6 H, dd)
(1H, CDC13) 5 ppm 7.67 (1 H, d), 7.44 (1 H, d), 7.39 (1 H, s), 6.38 (1 H, s), 5.00 (2
H, s), 4.50 - 4.36 (2 H, m), 4.21 (2 H, t), 4.03 — 3.95 (1 H, m), 3.91 — 3.61 (5 H, m),
3.49 (1 H, dd), 3.01 (2 H, t)
(1H, CDC13) 5 ppm 7.64 - 7.58 (1 H, m), 7.24 — 7.19 (1 H, m), 7.13 (1 H, s), 6.35
(1 H, s), 4.49 - 4.36 (2 H, m), 4.25 — 4.17 (2 H, m), 4.03 — 3.95 (1 H, m), 3.90 —
3.61 (5 H, m), 3.54 — 3.45(1 H, m), 3.02 — 2.95 (2 H, m), 2.81 - 2.72 (2 H, m), 1.59
— 1.49 (2 H, m), 0.77 — 0.64 (1 H, m), 0.49 - 0.42 (2 H, m), 0.10 - 0.02 (2 H, m)
(1H, CDC13) 5 ppm 7.66 (1 H, d), 7.33 (1 H, d), 7.29 (1 H, s), 6.36 (1 H, s), 4.50 (2
H, s), 4.47 - 4.35(2 H, m), 4.19 (2 H, t), 4.07 — 3.93 (2 H, m), 3.90 — 3.60 (5 H, m),
3.48 (1 H, t), 3.00 (2 H, t), 1.82 - 1.70 (6 H, m), 1.62 - 1.50 (2 H, m)
(1H, CDC13) 5 ppm 7.64 (1 H, d), 6.91 (1 H, dd), 6.80 (1 H, s), 6.28 (1 H, s), 6.11 —
6.01 (1 H, m), 5.45 (1 H, dd), 5.34 (1 H, dd), 4.61 (2 H, dd), 4.47 - 4.37 (2 H, m),
4.21 (2 H, t), 4.03 — 3.95 (1 H, m), 3.89 — 3.64 (5 H, m), 3.49 (1 H, t), 2.98 (2 H, t)
(1H, CDC13)6 ppm 7.63 (1 H, d), 6.91 (1 H, dd), 6.80 (1 H, d), 6.28 (1 H, s), 6.11 —
6.01 (1 H, m), 5.44 (1 H, m), 5.34 (1 H, dd), 4.61 (2 H, dt), 4.47 - 4.37 (2 H, m),
4.21 (2 H, t), 4.03 — 3.95 (1 H, m), 3.89 — 3.63 (5 H, m), 3.49 (1 H, dd), 2.98 (2 H,
WO 92791
de# NMR data (8)
(1H, CDC13) 5 ppm 7.68 (1 H, d), 7.36 (1 H, d), 7.31 (1 H, s), 6.41 — 6.38 (1 H, m),
4.61 (2 H, s), 4.47 - 4.37 (2 H, m), 4.25 — 4.17 (2 H, m), 3.99 (3 H, dt), 3.89 — 3.60
(6 H, m), 3.53 — 1.94 (2 H, m), 1.74
— 3.43 (3 H, m), 3.02 (2 H, t), 2.01 - 1.64 (2 H,
(1H, CDC13) 5 ppm 8.62 (1 H, br. s.), 8.53 (1 H, br. s.), 7.73 (1 H, d), 7.64 (1 H, d),
7.41 (1 H, dd), 7.35 (1 H, s), 7.29 (1 H, d), 6.36 (1 H, s), 4.48 - 4.34 (2 H, m), 4.20
(2 H, t), 4.03 — 3.93 (3 H, m), 3.89 — 3.61 (7 H, m), 3.48 (1 H, dd), 2.99 (2 H, t)
(1H, CDC13) 5 ppm 7.60 (1 H, d), 7.19 (1 H, dd), 7.10 (1 H, s), 6.34 (1 H, s), 4.49 -
4.34 (2 H, m), 4.20 (2 H, t), 4.02 - 3.93 (1 H, m), 3.90 - 3.60 (5 H, m), 3.48 (1 H,
dd), 2.98 (2 H, t), 2.64 (2 H, t), 1.63 (2 H, m), 1.37 - 1.29 (4 H, m), 0.94 - 0.86 (3
H, m)
(1H, CDC13) 5 ppm 7.63 (1 H, d), 7.39 (1 H, dd), 7.31 (1 H, s), 6.36 (1 H, s), 4.50
- 4.39 (2 H, m), 4.20 (2 H, t), 4.02 — 3.98 (1 H, m), 3.89 — 3.66 (5 H, m), 3.49 (1 H,
t), 2.96 (2 H, t), 1.59 - 1.48 (1 H, m), 0.98 — 0.81 (4 H, m)
(1H, CDC13) 5 ppm 7.64 — 7.58 (1 H, m), 7.24 — 7.19 (1 H, m), 7.13 (1 H, s), 6.35
(1 H, s), 4.49 - 4.36 (2 H, m), 4.24 - 4.17 (2 H, m), 4.03 — 3.95 (1 H, m), 3.91 —
3.62 (5 H, m), 3.49 (1 H, dd), 3.03 — 2.95 (2 H, m), 2.81 — 2.73 (2 H, m), 1.59 —
1.50 (2 H, m), 0.71 (1 H, s), 0.49 — 0.42 (2 H, m), 0.09 — 0.03 (2 H, m)
(1H, CDC13) 5 ppm 7.69 (1 H, d), 7.35 (1 H, d), 7.30 (1 H, s), 6.38 (1 H, s), 4.82 —
4.75 (2 H, m), 4.72 - 4.64 (3 H, m), 4.49 (2 H, s), 4.48 - 4.37 (2 H, m), 4.21 (2 H,
dd), 4.03 — 3.95 (1 H, m), 3.90 — 3.62 (5 H, m), 3.49 (1 H, dd), 3.02 (2 H, t)
(1H, CDC13) 5 ppm 7.69 (1 H, d), 7.35 (1 H, d), 7.29 (1 H, s), 6.38 (1 H, s), 4.62 (2
H, s), 4.54 (2 H, d), 4.48 - 4.36 (4 H, m), 4.21 (2 H, t), 3.99 (1 H, ddt), 3.90 — 3.61
(5 H, m), 3.58 (2 H, s), 3.49 (1 H, dd), 3.02 (2 H, t), 1.36 (3 H, s)
(1H, CDC13) 5 ppm 7.50 (1 H, d), 6.63 (1 H, dd), 6.48 (1 H, s), 6.21 (1 H, s), 4.47 —
4.34 (2 H, m), 4.21 - 4.14 (2 H, m), 4.01 - 3.91 (1 H, m), 3.89 — 3.60 (5 H, m), 3.48
(1 H, dd), 2.98 (2 H, s), 2.90 (2 H, t), 1.36 (2 H, dd), 0.96 (6 H, s), 0.87 (3 H, t)
(1H, CDC13) 5 ppm 7.61 (1 H, d), 7.22 (1 H, d), 7.14 (1 H, s), 6.34 (1 H, d), 4.46 -
4.34 (2 H, m), 4.19 (2 H, t), 3.97 (1 H, td), 3.89 — 3.60 (5 H, m), 3.48 (1 H, t), 3.42
— 3.35 (1 H, m), 2.97 (2 H, t), 2.93 — 2.85 (2 H, m), 2.70 (1 H, m), 1.84 — 1.63 (3
H, m), 0.92 (6 H, dd)
(1H, CDC13) 5 ppm 7.51 (1 H, d), 6.63 (1 H, d), 6.49 (1 H, br. s.), 6.21 (1 H, s),
4.46 - 4.356 (2 H, m), 4.21 - 4.11 (2 H, m), 3.97 (1 H, ddt), 3.88 — 3.62 (5 H, m),
3.48 (1 H, dd), 3.10 (2 H, d), 2.91 (2 H, t), 1.61 (1 H, m), 1.47 - 1.26 (8 H, m),
0.97 — 0.88 (6 H, m)
WO 92791
de# NMR data (8)
(1H, CDC13) 5 ppm 7.63 (1 H, d), 6.93 (1 H, dd), 6.82 (1 H, d), 6.29 (1 H, s), 5.30
(1 H, s), 4.47 — 4.36 (2 H, m), 4.22 - 4.14 (4 H, m), 4.03 — 3.94 (1 H, m), 3.88 —
3.628 (7 H, m), 3.53 — 3.453 (4 H, m), 2.97 (2 H, t)
(1H, CDC13) 5 ppm 7.64 — 7.58 (1 H, m), 6.90 (1 H, dd), 6.80 (1 H, d), 6.29 — 6.24
(1 H, m), 4.46 - 4.32 (2 H, m), 4.22 - 4.12 (4 H, m), 4.01 — 3.90 (1 H, m), 3.88 —
3.54 (9 H, m), 3.46 (1 H, dd), 2.95 (2 H, s), 1.23 (3 H, t)
(1H, CDC13) 5 ppm 7.60 — 7.67 (1 H, m), 6.93 — 6.86 (1 H, m), 6.78 (1 H, d), 6.29
(1 H, s), 4.50 - 4.36 (2 H, m), 4.25 - 4.17 (2 H, m), 4.04 - 3.94 (1 H, m), 3.91 -
3.61 (7 H, m), 3.53 — 3.44 (1 H, m), 3.01 - 2.93 (2 H, m), 1.37 - 1.227 (1 H, m),
0.73 — 0.65 (2 H, m), 0.42 - 0.34 (2 H, m)
(1H, CDC13) 5 ppm 7.64 (1 H, d), 6.93 (1 H, s), 6.82 (1 H, d), 6.27 (1 H, s), 4.90 —
4.82 (1 H, m), 4.74 - 4.67 (1 H, m), 4.48 - 4.28 (3 H, m), 4.26 - 4.14 (3 H, m), 4.03
— 3.91 (1 H, m), 3.90 — 3.58 (5 H, m), 3.53
— 3.41 (1 H, m), 3.03 - 2.91 (2 H, m)
(1H, CDC13) 5 ppm 7.64 (1 H, s), 7.48 — 7.40 (1 H, m), 7.40 — 7.35 (1 H, m), 6.40 —
6.34 (1 H, m), 4.47 (4 H, s), 4.28 — 4.15 (1 H, m), 3.93 — 3.56 (10 H, m), 3.43 (5 H,
s), 3.06 — 2.95 (2 H, m)
(1H, CDC13) 5 ppm 7.65 (1 H, d), 7.47 — 7.41 (1 H, m), 7.38 (1 H, s), 6.37 (1 H, s),
4.37 — 4.49 (4 H, m), 4.26 - 4.17 (2 H, m), 3.99 (1 H, m), 3.93 - 3.44 (12 H, m),
3.05 — 2.94 (2 H, m), 1.25 (3 H, t)
(1H, CDC13) 5 ppm 7.66 (1 H, d), 7.47 — 7.42 (1 H, m), 7.40 (1 H, s), 6.37 (1 H, s),
4.73 — 4.67 (1 H, m), 4.62 - 4.54 (1 H, m), 4.49 (4 H, s), 4.26 - 4.16 (2 H, m), 4.04
— 3.95 (1 H, m), 3.94 — 3.60 (7 H, m), 3.56 — 3.43 (1 H, m), 3.05 — 2.96 (2 H, m)
(1H, CDC13) 5 ppm 7.68 (1 H, d), 7.35 (1 H, d), 7.30 (1 H, s), 6.38 (1 H, s), 4.57 (2
H, s), 4.50 - 4.36 (2 H, m), 4.27 — 4.17 (2 H, m), 4.06 — 3.92 (1 H, m), 3.92 — 3.60
(5 H, m), 3.57 — 3.44 (1 H, m), 3.17 (2 H, s), 3.09 — 2.96 (2 H, m), 0.97 (9 H, s)
(1H, CDC13) 5 ppm 7.70 — 7.64 (1 H, m), 7.40 — 7.33 (1 H, m), 7.31 (1 H, s), 6.37
(1 H, s), 4.59 (2 H, s), 4.50 — 4.35 (2 H, m), 4.27 - 4.16 (2 H, m), 4.07 - 3.94 (1 H,
m), 3.93— 3.59 (5 H, m), 3.57 — 3.44 (1 H, m), 3.45 — 3.34 (1 H, m), 3.08 — 2.96 (2
H, m), 2.05 - 1.90 (2 H, m), 1.82 - 1.71 (2 H, m), 1.48 - 1.18 (6 H, m)
(1H, CDC13) 5 ppm 7.68 (1 H, d), 7.37 (1 H, d), 7.32 (1 H, s), 6.38 (1 H, s), 4.58 (2
H, s), 4.51 - 4.36 (2 H, m), 4.26 — 4.176 (2 H, m), 4.05 — 3.94 (1 H, m), 3.92 — 3.61
(5 H, m), 3.54 — 3.44 (1 H, m), 3.38 (2 H, d), 3.07 — 2.98 (2 H, m), 1.20 — 1.05 (1
H, m), 0.63 — 0.54 (2 H, m), 0.29 - 0.20 (2 H, m)
2012/076275
de# NMR data (8)
(1H, CDC13) 5 ppm 7.62 (1 H, s), 6.91 (1 H, m), 6.81 (1 H, m), 6.27 (1 H, s), 4.41
139 (2 H, s), 4.25 — 1.84 (1
— 4.21 (2 H, m), 4.10 _ 3.41 (12 H, m), 2.96 (2 H, t), 2.01
H, m), 1.76 — 1.36 (5 H, m)
(1H, DMSO-d6) 5ppm 7.91 (1 H, d), 7.28 — 7.18 (2 H, m), 6.60 (1 H, s), 4.32 — 4.17
(2 H, m), 4.07 — 3.96 (2 H, m), 3.92 — 3.71 (3 H, m), 3.70 — 3.43 (4 H, m), 3.38 (2
H, m), 3.03 — 2.91 (2 H, m), 2.78 — 2.58 (2 H, m), 1.68 — 1.58 (2 H, m), 1.08 (3 H,
(1H, CDC13) 5 ppm 7.70 — 7.58 (1 H, d), 6.95 — 6.82 ( 1 H, d), 6.77 (1 H, s), 6.27 (1
H, s), 4.50 - 4.32 (2 H, m), 4.38- 4.15 (2 H, m), 4.05 — 3.92 (3 H, m), 3.92 — 3.60
(5 H, m), 3.55 — 3.42 (1 H, t), 3.05 — 2.92 (2 H, m), 1.85 - 1.70 (2 H, m), 1.40 -
1.30 (2 H, m), 0.92 (9 H, s)
(1H, CDC13) 5 ppm 7.61 (1 H, d), 7.21 (1 H, d), 7.13 (1 H, s) 6.35 (1 H, s), 4.46 —
4.40 (2 H, m), 4.20 (2 H, t), 3.99 — 3.97 (1 H, m), 3.87 — 3.65 (5 H, m), 3.49(1 H,
t), 3.39 (3 H, s), 3.00 — 2.93 (3 H, m), 2.83 — 2.82 (1 H, m), 2.66 - 2.64 (1 H, m),
1.95 — 1.91 (1 H, m), 1.75 — 1.73 (2 H, m), 0.90 (6 H, t)
(1H, CDC13) 5 ppm 7.66 — 7.60 (1 H, m), 6.91 — 6.86 (1 H, m), 6.80 — 6.76 (1 H, m),
6.28 (1 H, s), 4.48 - 4.35 (2 H, m), 4.24 - 4.17 (2 H, m), 4.11 - 4.04 (2 H, m), 4.02
— 3.95 (1 H, m), 3.91 — 3.61 (5 H, m), 3.54 — 3.45 (1 H, m), 3.03 - 2.94 (2 H, m),
1.98 — 1.88 (2 H, m), 1.45 — 1.36 (2 H, m), 0.78 — 0.66 (1 H, m), 0.50 — 0.43 (2 H,
m), 0.09 — 0.03 (2 H, m)
(1H, CDC13) 5 ppm 7.47 (1 H, d), 6.55 — 6.48 (1 H, m), 6.40 — 6.34 (1 H, m), 6.18
(1 H, s), 4.47 - 4.33 (2 H, m), 4.22 - 4.12 (2 H, m), 4.02 - 3.92 (1 H, m), 3.83 (5 H,
dd), 3.53 — 3.43 (1 H, m), 3.40 — 3.28 (1 H, m), 2.89 (2 H, t), 2.13 - 1.98 (2 H, m),
1.86 — 1.73 (2 H, m), 1.73 — 1.63 (1 H, m), 1.50 - 1.11 (5 H, m)
(1H, DMSO-d6) 5 ppm 7.95 — 7.87 (1 H, m), 7.29 — 7.19 (2 H, m), 6.60 (1 H, s),
4.54 - 4.44 (1 H, m), 4.29 - 4.21 (2 H, m), 4.07 — 3.97 (2 H, m), 3.91 — 3.72 (3 H,
m), 3.70 — 3.54 (2 H, m), 3.54 — 3.43 (1 H, m), 3.43 — 3.34(1 H, m), 3.06 — 2.81 (4
H, m), 2.63 - 2.52 (1 H, m), 1.81 - 1.64 (1 H, m), 1.52 - 1.36 (1 H, m), 0.81 (9 H,
(H, CDC13) 5 ppm 7.68 (1 H, d), 7.38 — 7.32 (1 H, m), 7.30 (1 H, s), 6.38 (1 H, s),
4.56 (2 H, s), 4.50 — 4.36 (2 H, m), 4.26 - 4.18 (2 H, m), 4.04 - 3.94 (1 H, m), 3.94
— 3.5994 (4 H, m), 3.55 — 3.44 (1 H, m), 3.40 (2 H, d), 3.07 — 2.98 (2 H, m), 2.30 —
2.16 (1 H, m), 1.86 - 1.72 (2 H, m), 1.66 - 1.51 (5 H, m), 1.35 - 1.20 (2 H, m)
(1H, CDC13) 5 ppm 7.61 (1 H, d), 7.18 (1 H, dd), 7.12 (1 H, d), 6.35 (1 H, s), 4.46
- 4.36 (2 H, m), 4.21 (2 H, t), 4.00 — 3.97 (1 H, m), 3.88 — 3.64 (5 H, m), 3.49 (1 H,
t), 3.34 — 3.30 (4 H, m), 2.98 (2 H, t), 2.81 — 2.60 (2 H, m), 1.89 - 1.676 (2 H, m),
1meHm
WO 92791
de# NMR data (8)
(1H, CDC13) 8 ppm: 7.62 (1 H, d), 7.23 — 7.13 (4 H, m), 6.71 (1 H, t), 6.58 (2 H, d),
6.12 (1 H, s), 4.47 - 4.37 (2 H, m), 4.21 (2 H, t), 4.08 — 3.98 (1 H, m), 3.88 — 3.63
(6 H, m), 3.49 (1 H, t), 3.17 (2 H, t), 2.98 (2 H, t), 2.79 (2 H, t), 2.01 - 1.94 (2 H,
(1H, CDC13) 8 ppm 7.61 (1 H, d), 7.20 (1 H, d), 7.12 (1 H, s), 6.35 (1 H, s), 4.47 —
4.37 (2 H, m), 4.21 (2 H, t), 4.01 — 3.97 (1 H, m), 3.88 — 3.63 (6 H, m), 3.49 (1 H,
t), 2.98 (2 H, t), 2.69 (2 H, t), 1.89 - 1.62 (2 H, m), 1.52 -145 (2 H, m), 1.31 -
1.30 (1 H, m), 1.20 (3 H, d)
(1H, CDC13) 8 ppm 7.61 (1 H, d), 7.20 (1 H, d), 7.12 (1 H, s), 6.35 (1 H, s), 4.47 —
4.37 (2 H, m), 4.21 (2 H, t), 4.01 — 3.97 (1 H, m), 3.88 — 3.63 (7 H, m), 3.49 (1 H,
t), 2.98 (2 H, t), 2.70 (2 H, t), 1.76 - 1.60 (4 H, m), 1.31 - 1.26 (1 H, m)
(1H, CDC13) 8 ppm 7.57 — 7.50 (1 H, m), 6.71 (1 H, d), 6.53 (1 H, br. s.), 6.21 (1 H,
), 4.513 - 4.33 (2 H, m), 4.26 — 4.14 (2 H, m), 4.06 — 3.93 (1 H, m), 3.92 — 3.56 (6
H, m), 3.56 — 3.41 (1 H, m), 3.00 — 2.90 (2 H, m), 2.88 (3 H, s), 2.04 — 1.63 (2 H,
m), 1.60 — 1.31 (5 H, m), 1.28 - 1.08 (1 H, m)
(1H, CDC13) 8 ppm 7.52 — 7.46 (1 H, m), 6.55 — 6.50 (1 H, m), 6.40 — 6.36 (1 H, m),
6.19 (1 H, s), 4.48 - 4.33 (2 H, m), 4.23 — 4.13 (2 H, m), 4.04 — 3.92 (1 H, m), 3.85
(5 H, d), 3.56 — 3.42 (1 H, m), 3.06 — 2.99 (2 H, m), 2.93 - 2.84 (2 H, m), 1.92 -
1.50 (6 H, m), 1.36 — 1.12 (3 H, m), 1.08 - 0.91 (2 H, m)
(1H, CDC13) 8 ppm 7.50 (1 H, d), 6.59 — 6.49 (1 H, m), 6.44 — 6.35 (1 H, m), 6.20
(1 H, s), 4.49 - 4.33 (2 H, m), 4.24 - 4.13 (2 H, m), 4.05 — 3.93 (3 H, m), 3.92 —
3.59 (5 H, m), 3.56 — 3.32 (3 H, m), 3.16 — 3.07 (2 H, m), 2.96 — 2.84 (2 H, m), 1.98
— 1.80 (1 H, m), 1.79 - 1.64 (2 H, m), 1.428 - 1.28 (2 H, m)
(1H, CDC13) 8 ppm 7.54 — 7.46 (1 H, m), 7.14 — 7.08 (1 H, m), 7.04 (1 H, s), 6.23
(1 H, s), 4.35 - 4.21 (2 H, m), 4.13 — 3.99 (2 H, m), 3.91 — 3.80 (1 H, m), 3.79 —
3.45 (5 H, m), 3.41 — 3.30 (1 H, m), 2.86 (2 H, t), 2.64 — 2.54 (2 H, m), 1.67 — 1.58
(2 H, m), 1.45 (4 H, d), 0.80 (6 H, m)
(1H, CDC13) 8 ppm 7.60 (1 H, d), 7.23 — 7.19 (1 H, m), 7.13 (1 H, s), 6.34 (1 H, s),
4.45 - 4.35 (2 H, m), 4.18 (2 H, t), 4.02 - 3.92 (1 H, m), 3.82 (5 H, m), 3.48 (1 H,
dd), 2.97 (2 H, br. t), 2.79 — 2.70 (2 H, m), 1.82 — 1.74 (2 H, m), 1.30 (6 H, s)
(1H, CDC13) 8 ppm 7.64 — 7.59 (1 H, m), 7.25 — 7.20 (1 H, m), 7.14 (1 H, s), 6.35
(1 H, s), 4.48 - 4.35 (2 H, m), 4.24 - 4.16 (2 H, m), 4.02 — 3.94 (1 H, m), 3.90 —
3.44 (7 H, m), 3.02 - 2.95 (2 H, m), 2.92 — 2.81 (1 H, m), 2.78 — 2.67 (1 H, m), 1.87
- 1.68 (2 H, m), 1.62 - 1.42 (2 H, m), 0.96 (3 H, s)
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de# NMR data (8)
(1H, CDC13) 8 ppm 7.70 — 7.56 (1 H, d), 6.95 — 6.85 (1 H, d), 6.80 (1 H, s), 6.28 (1
158 H, s), 4.50 — 4.35 (2 H, m), 4.25 - 4.10 (2 H, m), 4.05 — 3.92 (1 H, m), 3.10 — 3.57
(8 H, m), 3.55 — 3.40 (1 H, m), 3.05 — 2.90 (2 H, m), 1.05 (9H, s)
(1H, CDC13) 8 ppm 7.63 (1 H, d), 6.88 (1 H, dd), 6.77 (1H, d), 6.28 (1 H, s), 4.46 —
4.36 (2 H, m), 4.20 (2 H, t), 4.05 — 3.96 (3 H, m), 3.88 — 3.65 (7 H, m), 3.51 — 3.43
(3 H, m), 2.97 (2 H, t), 2.12 - 2.01 (1 H, m), 1.78 - 1.75 (2 H, m), 1.59 - 1.42 (2 H,
(1H, CDC13) 8 ppm 7.63 (1 H, d), 7.35 — 7.18 (1 H, m), 7.12 (1H, s), 6.36 (1 H, s),
4.50 - 4.35 (2 H, m), 4.28 — 4.15 (2 H, m), 4.05 — 3.95 (1 H, m), 3.95 — 3.60 (5 H,
m), 3.55 — 3.42 (1 H, m), 3.05 — 2.90 (2 H, m), 2.75 — 2.60 (2 H, m), 1.80 — 1.65 (2
H, m), 1.55 - 1.48 (2 H, m), 1.22 (6 H, s)
(1H, CDC13) 8 ppm 7.68 (1 H, d), 7.34 (1 H, d), 7.29 (1 H, s), 6.38 (1 H, s), 4.55 (2
H, s), 4.48 — 3.96 (3 H, m), 3.91
- 4.38 (2 H, m), 4.22 (2 H, t), 4.02 — 3.61 (5 H,
m), 3.55 — 3.35 (5 H, m), 3.02 (2 H, t), 2.00 — 1.86 (1 H, m), 1.69 (2 H, dd), 1.38 (2
H, dd)
(1H, CDC13) 8 ppm 7.68 — 7.62 (1 H, m), 6.95 — 6.87 (1 H, m), 6.82 — 6.77 (1 H, m),
6.29 (1 H, s), 4.51 — 4.35 (2 H, m), 4.26 - 4.17 (2 H, m), 4.05 - 3.92 (1 H, m), 3.91
— 3.60 (8 H, m), 3.55 — 3.44 (1 H, m), 3.04 - 2.94 (2 H, m)
(1H, CDC13) 8 ppm 7.64 (1 H, d), 6.91 (1 H, dd), 6.81 (1 H, d), 6.29 (1H, s), 4.91
(2 H, t), 4.56 (2 H, t), 4.47 - 4.36 (2 H, m), 4.26 (2H, d), 4.21 (2 H, t), 4.00 — 3.96
(1 H, m), 3.88 — 3.63 (5 H, m), 3.51 — 3.45 (2 H, m), 2.98 (2H, t)
(1H, DMSO-d6) 8 ppm 7.93 (1 H, d), 6.97 — 6.92 (2 H, m),6.53 (1 H, s), 4.24 — 4.23
(2H, m), 4.08 (2 H, t), 4.00 (2 H, t), 3.98 — 3.74 (3 H, m), 3.68 — 3.57 (2 H, m),
3.51— 3.48 (1 H, m), 3.37 (1 H, t), 2.96 (2 H, t), 1.84 — 1.80 (2 H, m), 1.36 — 1.30
(2 H, m), 0.81 — 0.63 (1 H, m), 0.42 — 0.39 (2 H, m), 0.04 — 0.02 (2 H, m)
(1H, CDC13) 8 ppm 7.65 (1 H, d), 7.24 (1H, dd), 7.16 (1H, s), 6.38 (1 H, s), 4.49 —
4.40 (2 H, m), 4.24 (2 H, t), 4.02 - 4.00 (1 H, m), 3.89 — 3.66 (3 H, m), 3.52 (3 H,
m), 3.43 (2 H, t), 3.38 (3 H, s), 3.02 (2H, t), 2.78 (2 H, t), 1.96 - 1.92 (2 H, m)
(1H, CDC13) 8 ppm 7.61 (1 H, d), 7.23 (1H, dd), 7.15 (1H, s), 6.35 (1 H, s), 4.46 —
4.36 (2 H, m), 4.20 (2 H, t), 4.01 — 3.95 (1 H, m), 3.88 — 3.62 (5 H, m), 3.49 (1 H,
t), 2.98 (2 H, t), 2.85 - 2.81 (2 H, m), 2.13 (1H, br s), 1.93 - 1.79 (4 H, m), 1.72 —
1.55 (6 H, m)
(1H, CDC13) 8 ppm 7.59 (1 H, d), 7.37 (1H, dd), 7.15 (1H, s), 6.34 (1 H, s), 4.44 -
167 4.35 (2 H, m), 4.17 (2 H, t), 4.01 — 3.92 (3 H, m), 3.88 — 3.60 (7 H, m), 3.47 (1 H,
t), 2.94 (2 H, t), 2.07 - 2.02 (2 H, m), 1.95-1.88 (2H, m)
de# NMR data (8)
(1H, CDC13) 5 ppm 7.66 (1 H, d), 7.23 (1H, dd), 7.17 (1H, s), 6.39 (1 H, s), 4.51 —
168 4.40 (2 H, m), 4.24 (2 H, t), 4.09 — 3.96 (1 H, m), 3.93— 3.65 (5 H, m), .49
(1H, m), 3.44 (2 H, t), 3.40 (3H, s), 3.02 (2 H, t), 2.79 (2 H, t), 2.00-1.89 (2H, m)
(1H, CDC13)6 ppm 7.55 (1 H, d), 7.16 (1H, dd), 7.08 (1H, s), 6.29 (1 H, s), 4.41 —
4.29 (2 H, m), 4.13 (2 H, t), 3.95 — 3.86 (1 H, m), 3.81- 3.54 (5 H, m), 3.46-3.38
(1H, m), 2.91 (2 H, t), 2.78-2.72 (2H, m), 1.87-1.75 (4 H, m), 172-153 (6 H, m)
(1H, CDC13) 5 ppm 7.66 (1 H, d), 6.95 (1H, dd), 6.84 (1H, s), 6.31 (1 H, s), 4.50 —
4.39 (2 H, m), 1 (4 H, m), 4.05 — 3.98 (1 H, m), 3.91— 3.65 (7 H, m), 3.55—
3.49 (3H, m), 3.00 (2 H, t), 1.71-1.62 (2 H, m), 0.96 (3 H, t)
(1H, CDC13) 5 ppm 7.65 (1 H, d), 6.94 (1H, dd), 6.83 (1H, s), 6.31 (1 H, s), 4.50 —
4.39 (2 H, m), .18 (4 H, m), 4.04 — 3.97 (1 H, m), 3.91— 3.65 (8 H, m), 3.51
(1H, t), 3.00 (2 H, t), 1.23 (6 H, d)
(1H, CDC13) 5 ppm 7.67 (1 H, d), 6.95 (1H, dd), 6.85 (1H, s), 6.31 (1 H, s), 4.50 —
4.40 (2 H, m), 425.421 (4 H, m), 4.05 — 3.98 (1 H, m), 3.91— 3.65 (7 H, m), 3.55—
3.49 (3H, m), 3.00 (2 H, t), .62 (2 H, m), 0.97 (3 H, t)
(1H, CDC13) 5 ppm 7.65 (1 H, d), 6.94 (1H, dd), 6.84 (1H, s), 6.31 (1 H, s), 4.50 —
4.40 (2 H, m), 4.26-4.19 (4 H, m), 4.04 — 3.97 (1 H, m), 3.92— 3.65 (8 H, m), 3.52
(1H, t), 3.00 (2 H, t), 1.23 (6 H, d)
(1H, CDC13) 5 ppm 7.64 (1 H, d), 7.22 (1H, dd), 7.15 (1H, s), 6.38 (1 H, s), 4.51 —
4.41 (2 H, m), 4.23 (2 H, t), 4.06 - 4.00 (1 H, m), 3.92— 3.66 (5 H, m), 3.57—3.50
(1H, m), 3.43 (2 H, t), 3.37 (3H, s), 3.01 (2 H, t), 2.71 (2 H, t), .61 (2H, m),
1.69-1.62 (2H,m)
Biological Examples
1. In vitro assays
1.1. Cell based assay: GTp-yS binding assay.
[00458] The following assay can be used for determination of GPR84 activation. The [3SS]GTPyS binding
assay measures the level of G protein activation following agonist occupation of a GPCR, by determining the
binding of the non-hydrolysable analog [35$]GTPyS to G01 subunits.
The assay is performed in a 96 well plate where the following reagents are added. First 50 uL
compound is added into the assay plate, ed by addition of 20 uL 3,3’ di indolylmethane at ECgo
concentration (concentration which gives 80% of the activity of GPR84). In a last step, 30 uL of a mixture
consisting of membranes-GTPyS-SpA beads is added [mixture consists of 20 ug/well membranes derived
from stable cell line over expressing GPR84 (membranes are pre-incubated with 0.1 uM GDP for 15 min at
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4°C), 0.1 nM [3SS]GTPyS (Perkin Elmer, NEG030) and 0.5 mg/well PVT-WGA SpA beads (Perkin Elmer,
RPNQ0001)]. All components are diluted in assay buffer containing 20mM HEPES pH 7.4; 5mM MgClZ;
250mM NaCl; 0.05% BSA; 75ug/mL saponin. ons are incubated for 90 min at room temperature
followed by centrifugation at 2000 rpm during 15 min. Plates are read on a Topcount reader (Perkin Elmer)
immediately after centrifugation (readout time, 1 min/well).
TABLE IV: GPR84 assa GT S IC 0 nM of selected Com ounds of the invention.
na: not active
* > 1001 nM
** 00 nM
***101-500 nM
**** 0.01- 100 nM
0\ DJ
O\O\ 0U)
O\O\ 600
ii\l\]
\I 4;
\l \0
0000000000000000
6066600 Lh-bwt—‘06 * *
de# GPR84
97 ***
****
101 ***
102 ***
103 ***
104 ****
105 ***
106 **
107 ****
108 ****
109 ****
110 ***
111 ***
112 ****
113 ***
114 ****
115 ****
116 ***
117 ***
118 ***
119 ***
120 ***
121 ****
122 ****
123 ****
124 ***
125 **
126 ****
127 **** * *
128 *** * *
129 ***
130 ***
131 ****
132 **
133 ***
134 ***
135 ***
136 ****
2. Cellular assays
2.1. Human neutrophil migration assay
[00461] We have established that GPR84 ts (MCFA such as sodiumdecanoate, 33’ di
indolylmethane and Embelin induce neutrophil chemo taxis and that GPR84 antagonists could block GPR84
agonist-induced chemo taxis but not IL8-induced chemotaxis, indicating that G Protein-Coupled Receptor 84
(GPR84) is an essential player in the s of phil recruitment.
The effect of agonists or antagonists for GPR84 can therefore be assayed in a neutrophil migration
test. In the neutrophil migration assay, neutrophils, freshly isolated from buffy coats from human volunteers,
are treated with a compound for 30 minutes. Subsequently, the neutrophils are transferred to the upper wells
of a Corning HTS transwell 96 permeable support system, of which the lower wells are filled with a n
solution at ECgo (concentration which gives 80% of the activity of GPR84). After 1 h of incubation,
migration of the neutrophils towards embelin in the lower compartment can be quantified by ing the
ATP-content of the lower wells using the ATPlite scence ATP detection assay system (Perkin Elmer,
Cat. N°.: 436110).
2.1.1 Isolation ofneutrophilsfrom human bufij} coat
A human buffy coat is diluted with an equal volume of ice cold DPBS. 20 mL of the diluted buffy
coat is gently mixed with 4 mL of ACD buffer (140 mM citric acid, 200 mM sodium citrate and 220 mM
dextrose). Then, 12 mL of the 6% dextran/0.9% NaCl solution (15 g n T2000 and 2.25 g NaCl
dissolved in 250 mL H20) is added to the mixture and the samples are inverted gently up to 20 times. The
total volume was transferred to a new recipient and ted at room temperature for 1 h for complete
separation of the two phases to occur. The ish supernatant is then erred to a clean centrifugation
tube and centrifiJged for 12 minutes at 1300 rpm and 4°C. After centrifiJgation, the supernatant is discarded
and the remaining cell pellet is rapidly resuspended in 12 mL of ice-cold H20 for red blood cell lysis to
occur. After 20 seconds, 4 mL of ice-cold 0.6 M KCl is added. Samples are mixed carefully and fuged
for 6 s at 1300 rpm, 4°C. The supernatant is discarded and the red blood cell lysis procedure is
repeated one more time. Subsequently, the cell pellet is resuspended in 4 mL of DPBS and layered over 5
mL of Lymphoprep (Nycomed Pharma, Cat. N°.: 1114545) in a 15 mL centrifuge tube. After centrifugation
for 12 min at 1300 rpm, 4°C, the supernatant is removed and the cell , containing the neutrophils, is
resuspended in 25 mL chemotaxis buffer (RPMI 1640 medium, supplemented with 10 mM HEPES; freshly
made for each experiment)
2. I .2 Migration assay
[00464] A cell suspension of 6 cells per milliliter is prepared. 20 uL of compound solution in
chemotaxis buffer is added to 180 uL cell suspension. The mixture is incubated at 37°C for 30 minutes with
intermediate resuspension of the cells after 15 minutes. Following this, 70 uL cell sion is transferred
to the upper compartment of a Corning HTS transwell 96 permeable support system with 5.0 um pore size
polycarbonate membrane (Corning, Cat.N°.: 3387). The receiver well of the transwell system is then filled
with 200 uL chemotaxis buffer containing compound and chemotactic agent (embelin). After incubation at
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37°C in 5% C02 for 1 h, the upper plate of the transwell system is removed and the cell suspension in the
er plate is transferred to a 96-well V-bottom plate. 50 uL of DPBS is added to the receiver plate to
prevent remaining cells from drying out. The V-bottom plate is centrifuged for 6 minutes at 1500 rpm. The
supernatant is removed and the cells are resuspended in 50 uL DPBS. The cells are then erred back to
the receiver plate of the transwell system. After this, 100 uL ATPlite on (Perkin Elmer, Cat. N°:
436110) was added to the cells. The plate is incubated for 10 minutes in the dark, while shaking. 170 uL of
cell lysate is then transferred to a white 96-well plate and luminescence is measured. The detected
luminescent signal is considered as linearely related to the number of cells having migrated from the upper
well to the receiver well.
TABLE VII: human neutro hil mi ration inhibition
* > 1001 nM
** 501-1000 nM
***101-500 nM
**** 0.01-100 nM
de# Neutrophils de# Neutrophils
*** ****
*** ****
*** ****
“— ****
****
****
****
****
****
****
****
****
*** ****
*** ****
****
****
****
m— ****
****
****
m— ****
m— ****
****
****
de# Neutrophils de# Neutrophils
— —
2.2. Rat neutrophil migration assay
We have established that GPR84 agonists (MCFA such as sodiumdecanoate, 3,3 ’ di
indolylmethane and Embelin induce neutrophil chemotaxis and that GPR84 antagonists could block GPR84
agonist-induced chemotaxis but not IL8-induced chemotaxis, indicating that G Protein-Coupled or 84
(GPR84) is an essential player in the s of neutrophil recruitment.
The effect of agonists or antagonists for GPR84 can therefore be assayed in a neutrophil migration
test. In the rat neutrophil migration assay, neutrophils, freshly isolated from rat after intraperitoneal injection
of glycogen (0.1 %, w/v), are d with a compound for 30 minutes. Subsequently, the neutrophils are
transferred to the upper wells of a Corning HTS transwell 96 permeable support , of which the lower
wells are filled with a embelin solution at EC80 (concentration which give 80% of the activity of the GPR84).
After 1 h of tion, ion of the neutrophils towards embelin in the lower compartment can be
quantified by measuring the ntent of the lower wells using the Cell Titer Glow Substrate assay system
(Promega, Cat.N°.: G755B).
2.2.1. Isolation ofneutrophilsfrom rats
24 h after intraperitoneal injection of glycogen (0.1 %, w/v), cells are harvested by peritoneal
lavage with 25mL HBSS then centrifuged for 12 minutes at 1300 rpm and 4°C. After centrifiJgation, the
supernatant is discarded and the remaining cell pellet is rapidly resuspended in 12 mL of ice-cold H20 for red
blood cell lysis to occur. After 20 seconds, 4 mL of ice-cold 0.6 M KCl is added. Samples are mixed
carefully and centrifuged for 6 minutes at 1300 rpm, 4°C. The supernatant is discarded and the cell pellet is
ended in 4 mL of DPBS and layered over 5 mL of Lymphoprep (Axis Shield, Cat. N°.: 1114544) in a
mL centrifuge tube. After centrifugation for 30 min at 1500 rpm, 4°C, the supernatant is removed and the
cell pellet, containing the neutrophils, is resuspended in 5 mL chemotaxis buffer (RPMI 1640 medium,
mented with 10 mM HEPES; y made for each experiment).
2.2.2. ion assay
A cell suspension of 8.9x106 cells per milliliter is ed. 10 [LL of compound solution in
chemotaxis buffer is added to 90 [LL cell suspension. The mixture is incubated at 37°C for 30 minutes with
intermediate resuspension of the cells after 15 minutes. Following this, 75 [LL cell suspension is transferred to
the upper tment of a Corning HTS transwell 96 permeable support system with 5.0 um pore size
polycarbonate ne (Corning, Cat.N°.: 3387). The receiver well of the transwell system is then filled
with 200 uL chemotaxis buffer ning compound and actic agent in). After incubation at
37°C in 5% C02 for 1 h, the upper plate of the transwell system is removed and 70 [LL Cell Titer Glow
Substrate (Promega, Cat.N°.: G755B) are added in the receiver plate. The receiver plate is incubated for 10
minutes in the dark, while shaking. 180 uL of cell lysate is then erred to a white 96-well plate and
scence is measured. The ed scent signal is considered as ely related to the number of
cells having migrated from the upper well to the receiver well.
3. ADME, PK and Safety Models
3.] Aqueous Solubility
Starting from a 10mM stock in DMSO, a serial dilution of the compound is prepared in DMSO.
The on series is transferred to a 96 NUNC Maxisorb plate F-bottom and 0.1M phosphate buffer pH 7.4
or 0.1M citrate buffer pH3.0 at room temperature is added.
The final concentrations range from 18.75 to 300 uM in 5 equal dilution steps. The final DMSO
concentration does not exceed 3%.
200uM Pyrene is added to the comer points of each 96 well plate and serves as a reference point
for calibration of Z-axis on the microscope.
The assay plates are sealed and incubated for 1 h at 37°C while shaking at 230rpm. The plates are
then scanned under a white light microscope, yielding individual pictures of the precipitate per concentration.
The precipitate is analyzed and converted into a number by a custom-developed software tool. The first
concentration at which the compound appears completely dissolved is the concentration reported, however
the true concentration lies somewhere between this concentration and one dilution step higher.
Solubility values are reported in uM and in ug/mL.
3.2. Thermodynamic solubility
Two individual solutions of 2 mg/mL of compound are prepared in a 0.1 M phosphate buffer pH
7.4 or a 0.1 M citrate buffer pH 3.0 at room temperature in a 2mL glass vial.
] After addition of a ic stir, the samples are stirred at room temperature for 24 h.
After 24 h, the vials are centrifuged 10 min at 1400 rpm. The supernatant of the sample is then
transferred to a MultiscreenR Solubility Plate (Millipore, MSSLBPCS 0) and filtered (10-12" Hg) with the aid
of a vacuum manifold into a clean Greiner polypropylene V-bottom 96 well plate. Per sample, two dilutions
(factor 10 and 100) are made in DMSO. Other dilutions can be made if the acquired peak area is not within
the standard curve.
A 10mM DMSO stock, made from dry matter, is used to make a 200ug/mL working stock. The
standard curve for the compound is prepared in DMSO starting from the 200ug/mL working stock. Eight
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concentrations and two quality control samples (QC) are made in 2mL tubes. The first 3 concentrations (50,
and 15 ug/mL) and the first QC sample (20ug/mL) are made starting with the 200ug/mL working stock.
The 4th concentration (5 ug/mL) is made with the 50ug/mL solution and the 5th concentration (1 ug/mL) with
the 15ug/mL. The last three concentrations (0.2, 0.1 and 0.05 ug/mL) are made with the 1 ug/mL solution. The
second QC sample (0.5ug/mL) is made with the first QC sample.
Of every step of the dilution series, quality control and sample dilutions, a volume is transferred to
a 96-well Deepwell plate. The samples are injected on a LC-MS/MS system (API2000 from d
Biosystems).
The s are analyzed on LC-MS/MS with a flow rate of 0.5mL/min. Solvent A is 0.1%
Formic Acid in water and solvent B is 0.1% Formic Acid in methanol. The sample is run under positive ion
spray on a Pursuit 5 C18 2.0mm column (Varian). The t nt has a total run time of 1.4 minutes
and ranges from 10% B to 100% B.
] The thermodynamic solubility samples are analyzed with the aid of QuanLynx software. For the
standard curve a linear or quadratic curve can be used in the analysis. Samples of the standard curve that have
more than 15% deviation are excluded; the lowest concentrations of the curve may vary up to 20%. Peak
areas of the samples are plotted against the standard curve to obtain the lity of the compound.
Solubility values are ed in uM or ug/mL.
3.3 Microsomal stability
[00483]A 10 mM stock solution of nd in DMSO is 1,668 fold diluted in a 105 mM phosphate buffer
pH 7.4. Of this compound dilution, 50 [LL is transferred in two 96 assay plates: one for time point 0 min (T0
plate) and one for time point 30 min (T30 plate) and pre-warmed at 37°C.
In the time zero reference sample (T0 plate), 100 uL MeOH (1 :1) is added to the wells. In each
assay plate (T0 and T30 min), 50 [LL of omal mix is then added.
[00485] Final reaction concentrations are: 3 uM compound, 0.5 mg/mL microsomes, 0.4 U/mL GDPDH,
3.3 mM MgC12, 3.3 mM glucosephosphate and 1.3 mM NADP+.
The T30 plate is incubated at 37°C, 300 rpm and after 30 minutes of incubation the reaction is
stopped with MeOH (1 :1). The samples are mixed, centrifuged and the supernatant is ted for analysis
on LC-MS/MS (API2000 from Applied Biosystems).
The samples are analyzed on LC-MS/MS with a flow rate of 0.5mL/min. Solvent A is 0.1%
Formic Acid in water and t B is 0.1% Formic Acid in methanol. The sample is run under positive ion
spray on a Pursuit 5 C18 2.0mm column (Varian). The solvent gradient has a total run time of 1.4 minutes
and ranges from 10% B to 100% B.Peak area from the parent compound at time 0 is considered to be 100%
remaining. The percentage remaining after 30 minutes incubation is ated from time 0 The solubility of
the compound in the final test concentration in buffer is inspected by microscope and results are also
3.4 cyte stability.
Test compounds (1 uM initial concentration, n=2) are incubated in Williams’ Medium E,
containing 4 mM L-gutamine and 2 mM magnesium sulphate, with pooled cryopreserved hepatocytes (Celsis
International) in suspension at cell densities of 025-05 million viable cells/mL. The incubations are
performed at 37°C in a shaking water bath with 100 uL samples taken from the incubation at 0, 10, 20, 45
and 90 minutes, and reactions terminated by addition of 100 uL of itrile containing carbamazepine as
analytical internal standard. Samples are centrifuged and the supernatant fractions analysed by MS.
The instrument responses (Le. peak heights) are referenced to the zero time-point samples (as 100%) in order
to determine the percentage of compound remaining. Ln plots of the % remaining for each compound are
used to determine the half-life for the hepatocyte incubations. Half-life values are calculated from the
onship: Tm (min) = -0.693/)t, where )t is the slope of the Ln concentration vs time curve. Standard
compounds testosterone, midazolam, and 4-methylumbelliferone are ed in the assay design.
3.5 Plasma Protein Binding (Equilibrium Dialysis)
A 10mM stock solution of the nd in DMSO is diluted with a factor 10 in DMSO. This
solution is further diluted in freshly thawed human, rat, mouse or dog plasma (BioReclamation INC) with a
final concentration of 5 uM and final DMSO tration of 0.5%.
A Pierce Red Device plate with inserts (ThermoScientific) is prepared and filled with 450uL PBS
in the buffer r and 300uL of the spiked plasma in the plasma chamber. The plate is ted for 4 h
at 37°C While shaking at 100rpm. After incubation, 120uL of both rs is transferred to 480uL
methanol in a 96-well round bottom, PP deep-well plates (Nunc) and sealed with an aluminum foil lid. The
samples are mixed and immediately centrifuged 30 min at 1400 rcf at 4°C and the supernatant is erred
to a 96 v-bottom PP plate (Greiner, 651201) for analysis on LC-MS/MS (API2000 from Applied
Biosystems).
The samples are analyzed on LC-MS/MS with a flow rate of 0.5mL/min. Solvent A is 0.1%
Formic Acid in water and solvent B is 0.1% Formic Acid in methanol. The sample is run under ve ion
spray on a Pursuit 5 C18 2.0mm column (Varian). The solvent gradient has a total run time of 1.4 minutes
and ranges from 10% B to 100% B.
Peak area from the compound in the buffer chamber and the plasma chamber are considered to be
100% compound. The percentage bound to plasma is derived from these results and is reported as percentage
bound to plasma.
The solubility of the compound in the final test concentration in PBS is inspected by microscope
to indicate whether itation is observed or not.
3.6 CacoZ bility
ectional Caco-2 assays are performed as described below. Caco-2 cells are obtained from
European Collection of Cell Cultures (ECACC, cat 86010202) and used after a 21 day cell culture in 24-well
Transwell plates (Corning, cell growth area: 033 cm2, Membrane pore size: 0.4 uM, membrane diameter: 6.5
mm)..
2x105 cells/well are seeded in plating medium ting of DMEM + GlutaMAXTM-I + 1%
NEAA + 10% FBS (FetalClone II) + 1% Pen/Strep. The medium is changed every 2 — 3 days.
Test and reference compounds (propranolol and rhodamine123 or vinblastine, all purchased from
Sigma) are prepared in Hanks’ Balanced Salt on containing 25 mM HEPES (pH7.4) and added to either
the apical (125 uL) or teral (600uL) chambers of the Transwell plate assembly at a concentration of 10
uM with a final DMSO concentration of 0.25%.
[00497] 50uM Lucifer Yellow (Sigma) is added to the donor buffer in all wells to assess integrity of the
cell layers by monitoring Lucifer Yellow permeation. As Lucifer Yellow (LY) cannot freely permeate
lipophilic barriers, a high degree of LY transport indicates poor integrity of the cell layer.
After a 1 h incubation at 37°C while shaking at an orbital shaker at 150rpm, 70uL aliquots are
taken from both apical (A) and basal (B) chambers and added to 100uL 50:50 acetonitrile:water solution
containing analytical internal standard (0.5uM azepine) in a 96 well plate.
r yellow is measured with a Spectramax Gemini XS (Ex 426nm and Em 538nm) in a clean
96 well plate containing 150uL of liquid from basolateral and apical side.
Concentrations of compound in the samples are measured by high performance chromatography
/mass spectroscopy (LC-MS/MS).
[00501] Apparent permeability (Papp) values are calculated from the relationship:
Papp = [compound1acceptor final X Vacceptor / ([compound1donor initial X Vdonor) /Tinc X Vdonor / surface area X 60 X 10
cm/s
V = chamber volume
Tinc = incubation time.
e area = 0.33cm2
The Efflux ratios, as an indication of active efflux from the apical cell surface, are calculated
using the ratio of Papp B>A/ Papp A>B.
The ing assay acceptance ia are used:
Propranolol: Papp (A>B) value 2 20(><10'6 cm/s)
Rhodamine 123 or Vinblastine: Papp (A>B) value < 5 (><10'6 cm/s) with Efflux ratio 25.
Lucifer yellow permeability: £100 nm/s
3.7 Liabilityfor QTprolongation
Potential for QT prolongation is assessed in the hERG manual patch clamp assay.
3. 7.1 Conventional whole-cellpalcn-clamp
cell patch-clamp recordings are performed using an EPC10 amplifier controlled by Pulse
V8.77 software (HEKA). Series resistance is typically less than 10 M9 and compensated by greater than
60%, recordings are not leak subtracted. Electrodes are manufactured from GC150TF pipette glass (Harvard).
The external bathing solution contains: 135 mM NaCl, 5 mM KCl, 1.8 mM CaClZ, 5 mM Glucose,
mM HEPES, pH 7.4.
The al patch pipette solution ns: 100mM Kgluconate, 20 mM KCl, 1mM CaClZ, 1 mM
MgC12, SmM NazATP, 2mM Glutathione, 11 mM EGTA, 10 mM HEPES, pH 7.2.
[00508] Drugs are perfused using a Biologic EVH-9 rapid ion system.
All recordings are performed on HEK293 cells stably expressing hERG channels. Cells are
cultured on 12 mm round lips (German glass, Bellco) anchored in the recording chamber using two
platinum rods (Goodfellow). hERG currents are evoked using an activating pulse to +40 mV for 1000 ms
followed by a tail current pulse to —50 mV for 2000 ms, holding potential is -80 mV. Pulses are applied every
20s and all experiments are med at room temperature.
3. 7.2 Data Analysis
IC50 values are calculated for each compound tested. The fold difference n the IC50 in the
manual hERG patch clamp and the d IC50 in the whole blood assay is calculated.
[00511] For the concentration response curves, peak tail current amplitude is measured during the voltage
step to -50 mV. Curve-fitting of concentration-response data is performed using the equation:
y=a+ [(b-a)/( 1+ 10A((10gC-X)d)]
where a is minimum response, b is maximum response and d is Hill slope, this equation can be
used to calculate both IC50 (where y = 50 and c is the IC50 value) and ICZO (where y = 20 and c is the ICZO
value). ad® Prism® pad® Software Inc.) software is used for all curve g. A difference of
100 fold or greater indicates a low potential for QT prolongation.
3.8 Pharmacokinetic study
3.8.1 Single dose pharmacokinetic study in rats
Compounds are ated in PEG200/physiological saline mixtures for the intravenous route and
in PEG400/0.5% methylcellulose (10/90 v/v) for the oral route. Test compounds are orally dosed as a single
esophageal gavage at 5-10 mg/kg and intravenously dosed as a bolus via the caudal vein at 1 mg/kg to male
Sprague-Dawley rats. Each group consists of 3 rats. Blood samples are collected either via the jugular vein
using cannulated rats or at the retro-orbital sinus with lithium heparin as anti-coagulant at the time points in
the following range: 0.05 to 8 h (intravenous , and 0.25 to 6 or 24 h (oral route). Whole blood samples
are centrifiJged at 5000 rpm for 10 min and the resulting plasma samples are stored at -20°C pending analysis.
3.8.2 Multiple dose pharmacokinetic study in rats
Compounds are formulated in PEG400/0.5% cellulose (10/90 v/v) for the oral route. Test
compounds are orally dosed as an esophageal daily gavage at 30 or 300 mg/kg to male Sprague-Dawley rats
for 14 days. Each group consists of 3 rats. Blood samples are collected via the tail vein with lithium heparin
as oagulant at the following time points on day 1, 7 and 14: 0.25, 1, 4, 8 and 24 h. In addition, on day 2
blood samples are taken at 0.25, 1 and 4 h and at day 4 and 11 at 0.25 h. Whole blood s are centrifuged
at 5000 rpm for 10 min and the resulting plasma samples are stored at -20°C pending is.
3.8.3 Quantification ofcompound levels in plasma
[00515] Plasma concentrations of each test compound are determined by an LC-MS/MS method in which
the mass spectrometer is operated in positive or negative electrospray mode.
3.8.4 Determination ofpharmacokineticparameters
Pharmacokinetic ters are calculated using Winnonlin® ight®, US).
3.9 7-Day rat toxicity study
A 7-day oral toxicity study with test compounds is performed in Sprague-Dawley male rats to
assess their toxic potential and toxicokinetics, at daily doses of 100, 300 and 1000 mg/kg/day, by gavage, at
the constant dosage-volume of 10 mL/kg/day.
[00518] The test compounds are formulated in PEG400/0.5% methylcellulose (10/90, v/v). Each group
includes 6 principal male rats as well as 3 satellite animals for toxicokinetics. A fourth group is given
PEG400/0.5% methylcellulose (10/90, v/v) only, at the same frequency, dosage volume and by the same
route of stration, and acts as the vehicle control group.
The goal of the study is to ine the lowest dose that results in no e events being
identified (no observable adverse effect level - NOAEL).
l 87
3.10 Cytochrome P450 inhibition
Reversible CYP inhibition and ependent CYP3A4 inhibition is determined in human liver
microsomes and specific probe substrates.
3.10.1 P450 inhibition in human liver microsomes, reversible inhibition
The inhibitory ial of a test compound is assessed for human cytochrome P450 isoenzymes
CYP1A2, 2C8, 2C9, 2C19, 2D6 and 3A4.
A 10 mM stock solution of the test compound is prepared in DMSO, serially diluted in Tris buffer
(100 mM pH 7.4) and added to hepatic microsomes (Xenotech LLC) and NADPH at 37°C in a shaking water
bath. Seven different test nds concentrations (0.05 to 100 uM), 1% DMSO and 1 mM NADPH are
obtained to react.
After 15 or 30 minutes reactions are terminated by on of 100 uL of acetonitrile containing
carbamazepine as analytical al standard. Samples are centrifuged and the supernatant fractions
analysed by MS. For each isoform, the instrument responses (peak heights) are referenced to those
for DMSO controls (considered as 100%) in order to determine the percentage ion in probe
metabolism, using midazolam and testosterone as probe substrate. Percentage inhibition of probe metabolism
and Log [test compound concentration] are plotted using ad Prism software. The sigmoidal dose
response model is fitted to the data in order to determine the IC50.
[00524] Inhibition of CYP3A4 using nifedipine and atorvastatin as probe substrate is carried out as
follows.
] A 1.67 mM stock solution of test nd is prepared in methanol, serially diluted 1:3 in 50
mM potassium phosphate buffer pH7.4 and added to human hepatic microsomes (BD Gentest) and probe
substrate. Seven different test compounds concentrations (0.045 - 33.3 uM), 2% methanol, 0.1 mg/mL
omes, 10 uM atorvastatin or 5 uM nifedipine. After pre-warming 5 minutes at 37°C, the reaction was
started by adding cofactor mix (7.65 mg/mL glucosephosphate, 1.7 mg/mL NADP, 6U/mL of e
phosphate dehydrogenase).
After 5 min (nifedipine) or 10 min (atorvastatin) at 37°C, the reaction (50 uL) is terminated with
150 uL acetonitrile:methanol (2: 1) solution with internal standard (Warfarin). Samples are centrifuged and
the supernatant fractions analyzed by LC-MS/MS. The instrument responses (ratio of test compound/internal
standard peak areas) are referenced to those for solvent controls (assumed as 100%) in order to determine the
tage reduction in probe metabolism. t of control activity vs tration plots are generated
and fitted using GraphPad Prism software to generate IC50.
3.10.2 CYP3A4 inhibition in human liver microsomes, lime-dependent
The time-dependent inhibitory ial of a test nd is assessed for human cytochrome
P450 isoenzyme 3A4. The compound is pre-incubated with the human liver microsomes before addition of
the probe substrates. The result is compared to the condition where the compound is not pre-incubated with
the human liver omes to see if there was a shift in IC50, indicating time-dependent inhibition.
A 10 mM stock solution of test compound is prepared in DMSO and d 1:20 with Tris buffer
(100 mM pH 7.4) and further serially diluted in Tris buffer/5% DMSO.
The cofactor, NADPH, and each test compound dilution is mixed in two separate plates for 0 and
min pre-incubation. Human hepatic microsomes (Xenotech LLC) are added only to the “30 minute pre-
incubation” plate and both plates are then incubated for 30 minutes at 37°C in a g water bath.
Following the pre-incubation, microsomes are added to the “0 minute” plate and riate probe ates
(in 0.5% DMSO) are added to both plates. Plates are then returned to the water bath for a further incubation.
In total, six different test compound concentrations (1.6 to 50 uM) are assessed. Reactions are
terminated with 100 uL of acetonitrile ning carbamazepine as analytical internal standard. Samples are
centrifuged and the supernatant fractions analysed by LC- MS/MS. For each isoform, the instrument
responses (peak height ratio with internal standard) are referenced to those for DMSO ls (considered as
100%) in order to determine the percentage reduction in probe lism. Percentage inhibition of probe
metabolism and Log [Test Compound concentration] are plotted using Graphpad Prism software. The
sigmoidal dose se model is fitted to the data in order to determine the IC50.
4. In-vivo s
The in-viv0 activity ofthe compounds ofthe invention may be demonstrated in the
following in vivo y inflammation models.
4.] Inflammatory bowel disease (mice).
The mouse chronic DSS—induced inflammatory bowel disease model (IBD) is a well validated
disease model for inflammatory bowel disease (Wirtz S. et al., 2007 Nature Protocols 2, 541-546; Sina C. et
al., 2009 J. Immunol. 183 7514-7522).
[00533] To induce a chronic colitis, female BALB/c mice are fed with 4% dextran sodium sulfate (DSS)
dissolved in drinking water for 4 days, followed by 3 days of regular drinking water. This cycle is ed
three times. This protocol allows inducing a strong colitis while avoiding high mortality rates. Animals are
divided into several groups:
a. intact water; e alone, n=10),
b. diseased (DSS; vehicle alone, n=10),
l 89
c. sulfazalazine used as reference (D88; 20 mg/kg/day, p.o., n=10) and
d. the tested compound (D88; 1, 3, 10, 30 mg/kg/day,p.o., n=10).
Clinical parameters are ed every other day. The disease actiVity index (DAI) is a
composite measure combining of the individual scores for weight loss, stool consistency and rectal
bleeding. Mice are sacrificed at day 20 of the ment according to the ol introduced by
Sina et al.(2009). At sacrifice time, the complete colon is removed and rinsed with sterile PBS.
Segments ofthe distal colon are dissected for histological is, gene expression and protein
level measurement.
4.2 Collagen-induced arthritis (mice).
The mouse collagen-induced arthritis (CIA) is the gold standard toid tis model
(Brand, er al., 2007 Nature Protocols 2, 1269- 1275, Lin er al., 2007 Br J Pharmacol 1, 829-831). DBA1//J
male mice are injected with a collagen II solution (Completed Freund’s adjuvant). Immune reaction is
boosted by a second injection plete Freund’s adjuvant) 21 days later. At day 31, arthritis is scored
according to the method of Khachigian er al. (Khachigian er al., 2006 Nature Protocols 1, 2512-2516) and
s are randomized to reach an average clinical score of 2 per group. Animals are divided into several
groups: intact (no treatment, n=5), diseased le alone, n=10), Enbrel® as reference (10 mg/kg, 3x week,
i.p., n=10), and the tested compound (3, 10 or 30 mg/kg/day, p.o., n=10). Therapeutic dosing lasted from day
31 to day 46 and the arthritis is scored every day. Mice are iced at day 46, X-ray photos are taken of the
hind paws of each individual animal and the severity of bone erosion is ranked with the radiological Larsen’s
score (Salvemini er al., 2001 Arthritis Rheum 44, 2909-2921).
4.3 Tabacco smoke model (mice)
Daily exposures of female inbred C57BL/6J mice to tobacco smoke (TS) for 11 consecutive days
result in pulmonary inflammation, as indicated by an increase in the total number of cells recovered in the
bronchoalveolar lavage (BAL), when compared with a similarly d air-exposed group, 24 h after the final
exposure. The exposure period to TS is increased initially from 25 minutes at the start of the study (day 1) to
a maximum of 45 minutes on day 3 until day 11. Animals are diVided into several groups: intact (no
ent, n=5), diseased (vehicle alone, n=10), Roflumilast as reference (5 mg/kg/day p.o., n=10), and the
tested compounds (10 or 30 mg/kg/bid, p.o., n=10). At the end of 11 days, the numbers of macrophages,
epithelial cells, phils and lymphocytes are counted in the BAL. BAL is further analysed for gene
expression and protein level. Lung tissue is dissected for histological analysis, gene expression and protein
level measurement.
It will be appreciated by those skilled in the art that the ing ptions are
exemplary and explanatory in nature, and intended to illustrate the invention and its preferred
embodiments. Through e experimentation, an artisan will recognise apparent modifications and
variations that may be made t departing from the spirit of the invention. All such modifications
coming within the scope of the appended claims are intended to be included therein. Thus, the
invention is intended to be d not by the above description, but by the following claims and their
equivalents.
All ations, including but not d to patents and patent applications, cited in this
specification are herein incorporated by reference as if each individual publication were specifically
and individually indicated to be incorporated by reference herein as though fully set forth.
It should be understood that factors such as the differential cell ation capacity of the
various compounds can contribute to discrepancies between the activity of the compounds in the in
vitro biochemical and cellular assays.
At least some of the chemical names of compound of the invention as given and set forth
in this application, may have been generated on an automated basis by use of a commercially ble
chemical naming software program, and have not been independently verified. Representative
programs performing this function include the Lexichem naming tool sold by Open Eye Software, Inc.
and the Autonom Software tool sold by MDL, Inc. In the instance where the indicated chemical name
and the depicted structure differ, the depicted structure will control.
[00541] Chemical structures shown herein were prepared using either ChemDraw® or ISIS®
/DRAW. Any open valency appearing on a carbon, oxygen or nitrogen atom in the structures herein
indicates the presence of a hydrogen atom. Where a chiral center exists in a structure but no specific
stereochemistry is shown for the chiral center, both enantiomers associated with the chiral structure are
encompassed by the structure.
] The reference in this specification to any prior ation (or information derived from
it), or to any matter which is known, is not, and should not be taken as an acknowledgment or
admission or any form of suggestion that that prior publication (or information derived from it) or
known matter forms part of the common l knowledge in the field of endeavour to which this
specification relates.
[00543] Throughout this specification and the claims which follow, unless the context requires
ise, the word "comprise", and variations such as "comprises" and ising", will be
understood to imply the inclusion of a stated integer or step or group of integers or steps but not the
exclusion of any other integer or step or group of integers or steps.
NCES
Wittenberger et al., 2001 J M01 Biol, 307, 799-813
Yousefi S et al., 2001 J Leukoc Biol, 69, 1045—52
Wang et al., 2006 The l of Biological Chemistry, 281 , 45, 34457-34464
Venkataraman et al., 2005, Immunology Letters, 101, 144-153
WO2007/027661 A2
Berry et al., 2010, , 466, 973-979
rd et al., 2007, Glia, 55:790-800
Bundgard, H., 1985 Design of Prodrugs, pp. 7-9, 21 -24, Elsevier, Amsterdam 1985
Part 8 of Remington’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton,
Pennsylvania
T. W. Greene and P. G. M. Wuts, 2006 Protecting Groups in c Synthesis, Wiley-Blackwell; 4th
Revised edition
Young Kim et al., 2007 Bioorganic & Medicinal Chemistry 15, 2667—2679
Le Pouls et al., 2003, The Journal of Biological Chemistry, 278, 28, 25481 -25489
Brown et al., 2003, The Journal ofBiological Chemistry, 278, 13, 11312-11319
Stoddart et al., 2008, Pharmacological Reviews, 60, 405-417
Wirtz S. et al., 2007 Nature Protocols 2, 541-546
Sina C. et al., 2009 J. Immunol. 183 7514-7522
Brand, et al., 2007 Nature Protocols 2, 1269- 1275
Lin et al., 2007 Br J col 1, 2
Khachigian et al., 2006 Nature Protocols 1 , 2512-2516
Salvemini et al., 2001 Arthritis Rheum 44, 2909-2921
Du Bois, 2010, Nat Rev, Drug Discovery, 9, 129
Nagasaki et.al., 2012, FEBS Letters, 586, 368—372
Claims (1)
1. A nd according to Formula Ia: O N wherein 5 R1 is H, Me, or halo; L1 is absent or is –O-, -S-, or -NR4a-; G is -W-L2-R2, or 10 R3; W is C1-4 alkylene, C2-4 alkenylene having one double bond, or C2-4 lene having one triple bond; L2 is absent or is –O-; R2 is 15 - H, - C1-8 alkyl, optionally substituted with one to three groups independently selected from o OH, o halo, o CN, 20 o C1-6 alkoxy, o C3-7 cycloalkyl, o 4-6 membered heterocycloalkyl comprising one to three heteroatoms independently selected from S, and O, o 5-6 membered heteroaryl comprising one to three heteroatoms independently 25 selected from N, S, and O, and o phenyl, - C4-7 cycloalkenyl comprising one double bond, H:\rbr\Interwoven\NRPortbl\DCC\RBR\9599805_1.docx-
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US201161578979P | 2011-12-22 | 2011-12-22 | |
US61/578,979 | 2011-12-22 | ||
PCT/EP2012/076275 WO2013092791A1 (en) | 2011-12-22 | 2012-12-20 | Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders |
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